Investigation By Condition/Syndrome

Conditions and Syndromes

10p13-14 Deletion Syndrome

Introduction

10p deletion syndrome is rare and has a prevalence of less than 1 in 1,000,000. The phenotype is dependant on the extent of the 10p deletion. Deletions of 10p encompassing the 10p13-14 boundary are associated with cardiac malformations and immune anomalies that overlap with the anomalies reported in the deletion 22q11 syndrome (DiGeorge syndrome/velocardiofacial syndrome). Due to the similarities in the malformations observed in the two syndromes, deletions of 10p13-14 are referred to as DiGeorge Syndrome/velocardiofacial syndrome complex 2 or DGS2. Features of 10p13-14 deletions include hypoparathyroidism, hypocalcemia, congenital conotruncal heart defects, thymus hypoplasia leading to T-cell deficiency and intellectual deficit. Facial features include an abnormally shaped skull, microcephaly, a long face, high forehead, broad nasal bridge, downslanting palpebral fissures, anteverted nares. However, patients also present with hand and foot abnormalities, genitourinary anomalies, hearing loss and severe psychomotor retardation, resulting in a clinical picture that clearly differs from that of the classic 22q11 deletion syndrome. Cases may arise as a new deletion or as a derivative or recombinant chromosome 10 inherited from a parent who carries a balanced chromosome rearrangement.

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1p36 Deletion Syndrome

Introduction

1p36 deletion syndrome has a prevalence of approximately 1 in 5000. Clinical features include learning difficulties (notably affecting speech) and behavioural problems, seizures, hypotonia, dysphagia, heart defects and hearing/vision defects. Facial features include deep-set eyes with straight eyebrows, midface hypoplasia, a broad, flat nose, long philtrum, and low-set, abnormally-shaped ears. This is the most common terminal deletion syndrome in humans but can also arise as an interstitial deletion. The size of the deletion varies between individuals. The majority of cases arise as a new deletion but in approximately 20% of cases the deletion is the result of a derivative chromosome 1 inherited from a parent who carries a balanced chromosome rearrangement.

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22q11 Deletion Syndrome

Introduction

22q11 deletion syndrome has a prevalence of approximately 1 in 5000. It is a contiguous gene syndrome caused by a 1.5 to 3.0 Mb deletion of 22q11.2. The deletion is also referred to as DiGeorge syndrome, Shprintzen syndrome or velocardiofacial syndrome. Clinical features include developmental delay, outflow tract defects of the heart (including tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch), hypocalcemia arising from parathyroid hypoplasia, and thymic hypoplasia. Facial features include cleft lip and palate, low-set ears, wide set eyes, a small jaw and a small philtrum. The majority of cases arise as a new deletion but in approximately 10% of cases the deletion is inherited from a parent.

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22q13.3 Deletion Syndrome

Introduction

22q13 deletion syndrome is a rare contiguous gene syndrome and has a prevalence of less than 1 in 1,000,000. The deletion is also referred to as Phelan McDermid syndrome. The deletion causes a broad spectrum of clinical features including neonatal hypotonia, global developmental delay, normal to accelerated growth, absent or severely delayed speech, and minor dysmorphic features. Common facial features include long eye lashes, large or unusual ears, relatively large hands, full brow, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of a particular gene on chromosome 22, SHANK3, is likely to be responsible for many of the syndrome's characteristic signs. The majority of cases arise as a new deletion but in approximately 15-20% of cases the deletion is the result of a derivative or recombinant chromosome 22 inherited from a parent who carries a balanced chromosome rearrangement.

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aCGH (Microarray) Testing

Introduction

Microarray Comparative Genomic Hybridisation (aCGH) is now offered as a first line test for paediatric referrals with developmental delay and/or congenital abnormalities, replacing karyotyping. This is a newer technology to identify chromosomal imbalance; it has a significantly higher resolution and a greater diagnostic yield (about 15% as compared to about 3%). Microarray testing can detect novel deletions or gains at a higher resolution than routine chromosome analysis as well as known microdeletion/duplication syndromes and recurrent microdeletions/duplications. Microarray testing cannot detect balanced chromosome rearrangements or polyploidy and may not detect unbalanced rearrangements present in mosaic form. For further information see our microarray page.

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Achondroplasia and Hypochondroplasia

Introduction

Achondroplasia is the most common form of disproportionate short stature in adults and children with an estamated prevalance of 1:27000. Hypochondroplasia is a milder chondrodystrophy that resembles true achondroplasia. It can be distinguished on clinical and radiographic grounds. Both are autosomal dominant disorders most commonly caused by sporadic mutations in the Fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4 at 4p16.3.

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AD-Multiple Epiphyseal Dysplasia

Introduction

Autosomal dominant Multiple Epiphyseal Dysplasia (AD-MED) is an osteochondrodysplasia affecting at least 1 in 10,000 individuals and is characterised by mild to moderate short stature and joint pain. AD-MED shows considerable genetic heterogeneity; mutations in the cartilage oligomeric matrix protein gene (COMP), the matrilin-3 gene (MATN3) and the genes encoding the α1, α2, and α3 chains of Type IX collagen (COL9A1, COL9A2, COL9A3) all cause AD-MED. Mutations remain undetected in approximately 10%-20% of individuals with MED, suggesting that unidentified additional genes are also involved in the pathogenesis of MED

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Aminoglycoside deafness mutation

Introduction

The mtDNA 1555A>G mutation in the MT-RNR1(12S) gene is is associated with aminoglycoside-induced and nonsyndromic hearing loss. The mutation is maternally inherited and predisposes to early age onset of hearing loss after exposure to ototoxic aminoglycosides; hearing loss may develop in individuals with the mtDNA m.1555A>G mutation independent of exposure to aminoglycosides, but usually with a later age of onset.

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Angelman Syndrome

Introduction

Angelman syndrome (AS) is a neurogenetic disorder (prevalence 1/12,000) causing delayed motor activities, learning difficulty, seizures, sleep disturbances, characteristic facial features and happy demeanour. Loss of the maternally contributed AS region can occur by five genetic mechanisms: deletion, paternal uniparental disomy, imprinting defects, mutation of the ubiquinin-protein ligase (UBE3A) gene and unidentified mechanisms.

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Aortic Aneurysm

Introduction

We simultaneously sequence 8 genes known to cause inherited aortic aneurism. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Arrhythmia/Cardiac Arrest

Introduction

We simultaneously sequence 19 genes known to cause inherited arrhythmia/cardiac arrest. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Introduction

We simultaneously sequence 6 genes known to cause inherited arrhythmogenic right ventricular cardiomyopathy (ARVC). We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Bloom Syndrome

Introduction

Bloom syndrome (BS) is a rare chromosomal breakage syndrome which has a prevalence of less than 1 in 1,000,000 (the exact prevalence is unknown). The main features are short stature, sun-sensitive skin changes (typically appear as a butterfly-shaped patch of reddened skin across the nose and cheeks), an increased risk of cancer (earlier onset of any cancer), and other health problems. Individuals often have a high-pitched voice and distinctive facial features including a long, narrow face; a small lower jaw; a large nose; and prominent ears. Bloom syndrome is an autosomal recessive inherited disorder, which means both copies of the gene in each cell have mutations. It is caused by a mutation in the BLM gene which is on chromosome 15 at 15q25.1. The BLM protein helps suppress sister chromatid exchanges and helps to maintain DNA stability during the copying process. The frequency of sister chromatid exchange increases about 10-fold in individuals with Bloom syndrome. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Bloom syndrome is more common in people of Central and Eastern European (Ashkenazi) Jewish background (1 in 50 000).

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BRCA1/2 mutation screening in FFPE samples to assist in the management of familial breast/ovarian cancer

Introduction

The management of families at high risk of having an inherited BRCA1/2 mutation where there is no living affected relative and/or no DNA sample is available, may benefit from BRCA1/2 mutation testing of archive pathology material. The test has been designed to perform on DNA extracted from typical formalin fixed paraffin embedded (FFPE) tissue specimens. BRCA1/2 mutation screening of FFPE tissue can identify germline pathogenic BRCA1/2 mutations in deceased relatives and a negative result can also reduce the likelihood that a pathogenic BRCA1/2 mutation is present in the family.

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Brugada Syndrome

Introduction

We simultaneously sequence 6 genes known to cause Brugada syndrome. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Cardiomyopathies

Introduction

We simultaneously sequence 37 genes known to cause inherited cardiomyopathy. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Introduction

We simultaneously sequence 4 genes known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT). We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Chromosome Analysis

Introduction

Cells from a variety of samples (chorionic villus, amniotic fluid, blood and solid tissue) are cultured. Chromosomes are visualised using the G-banding technique. Normal males and females carry 46 chromosomes; two of these are the sex chromosomes. Chromosome analysis can be used to detect numerical abnormalities where there is complete loss (e.g. Turner syndrome, 45,X) or gain (e.g. trisomy 21 or Down syndrome, 47,XY,+21) of a chromosome. It can also be used to detect structural chromosome changes where there is partial loss or gain of chromosome material. Chromosome analysis can also detect balanced structural anomalies such as reciprocal/Robertsonian translocations and inversions. We accept referrals encompassing a whole spectrum of referral reasons.

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Congenital Adrenal Hyperplasia

Introduction

CAH is an inherited disorder of steroidogenesis with a wide spectrum of expression. In about 95% of cases the condition is the result of 21-hydroxylase deficiency, an autosomal recessive condition mapping to the major histocompatibility complex on chromosome 6p21.3. The incidence of CAH based on biochemical criteria is 1 in14,000 including the non-classical form; a carrier frequency of 1 in 50 is used for risk calculations.

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Cri-du-Chat

Introduction

5p deletion syndrome, more commonly known as cri-du-chat (CDC) syndrome, has a prevalence of approximately 1 in 15,000 – 50,000. The phenotype is highly dependant on the extent of the deletion. Deletions can vary in size from extremely small and involving only band 5p15.2 (the critical region) to the entire p arm. As such, there is a broad spectrum of clinical features. Characteristic features of CDC syndrome in young children includes a high-pitched cat-like cry, microcephaly, round face, hypertelorism, micrognathia, epicanthic folds, broad nasal bridge, low-set ears, hypotonia, and severe psychomotor and mental disability. The characteristic cat-like cry without the typical dysmorphic features and severe developmental delay has been seen in individuals with a deletion confined to 5p15.3. Larger deletions tend to result in more severe intellectual disability and developmental delay than smaller deletions. With advancing age the clinical picture of CDC syndrome becomes less striking. Some of the clinical characteristics, such as long face, macrostomia, and scoliosis, become more evident. The majority of cases arise as a new deletion but in approximately 12% of cases the deletion is the result of a derivative or recombinant chromosome 5 inherited from a parent who carries a balanced chromosome rearrangement.

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Cystic Fibrosis

Introduction

Cystic Fibrosis, caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR at 7q31-32), is the most frequent autosomal recessive genetic disorder in caucasians of European origin. The incidence in the UK in this ethnic group is 1/2500. More than 1000 different mutations are known with the spectrum and frequency varying with ethnic background.

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Cystic Fibrosis (Rare)

Introduction

Cystic Fibrosis, caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR at 7q31-32), is the most frequent autosomal recessive genetic disorder in caucasians of European origin. The incidence in the UK in this ethnic group is 1/2500. More than 1000 different mutations are known with the spectrum and frequency varying with ethnic background. The most common variants are tested using commercial kits that achieve a sensitivity of ~90% in North Western caucasians. We offer molecular genetic testing for rare CFTR mutations which account for the remainder of cases of cystic fibrosis.

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Dilated Cardiomyopathy (DCM)

Introduction

We simultaneously sequence 22 genes known to cause inherited cardiomyopathy. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Down Syndrome

Introduction

Down syndrome (trisomy 21) occurs in approximately 1 in 1000 live births, making it the most common aneuploidy. It occurs in individuals who carry and extra chromosome 21 or extra chromosome 21 material, including the critical region at 21q22.3. The main features characteristic of trisomy 21 include distinctive facial features, mild to severe learning difficulties, congenital heart defects (particularly AVSD), gastrointestinal problems (such as duodenal atresia or stenosis), imperforate anus and Hirschsprung Disease. Facial features include down-slanting palperbral fissures, a flattened profile, Brushfield spots and a protruding tongue. The majority of cases are "free" trisomy 21, but in approximately 3.5% of cases the additional chromosome 21 material is the result of a derivative chromosome 21, which may be inherited from one parent who carries a balanced reciprocal translocation involving chromosome 21. Although free trisomy 21 occurs sporadically, there is an increased risk of a Down syndrome pregnancy with increasing maternal age. Trisomy 21 may also appear in a mosaic form, where normal cells are also present in the individual. These individuals may exhibit a milder phenotype, which is dependant on the extent and tissue distribution of the normal cell line.

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Duchenne and Becker Muscular Dystrophy

Introduction

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease appearing during childhood. In Becker muscular dystrophy (BMD) symptoms are similar but less severe and appear later. DMD and BMD are caused by mutations in the dystrophin gene at Xp21.Whole exon deletions are the predominant type of mutation (~65%). Whole exon duplications are seen in ~10% of cases.

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Edwards Syndrome

Introduction

Edwards Syndrome (trisomy 18), occurs in approximately 1 in 5000 live births. It is caused by an additional chromosome 18 or extra chromosome 18 material, including the critical region at 18q11-q12. The main features of Edwards syndrome include low birth weight, abnormally shaped head (microcephaly), hypotonia, characteristic facial features (such as small jaw, upturned nose, widely spaced eyes and malformed ears), rockerbottom feet, overlapping fingers and other congenital abnormalities of the heart, brain, kidneys, digestive tract and genitals. Many infants with trisomy 18 die within the first month and only 10% survive to one year. Although free trisomy 18 occurs sporadically, there is an increased risk of an Edwards syndrome pregnancy with increasing maternal age. Trisomy 18 may also appear in a mosaic form, where normal cells are also present in the individual. These individuals may exhibit a milder phenotype, which is dependant on the extent and tissue distribution of the normal cell line.

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Fabry Disease

Introduction

Fabry disease is an X-linked recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme alphagalactosidase A. This deficiency results in the gradual accumulation of ceramide trihexoside in the walls of the blood vessels and tissues such as the heart, kidneys, and brain, which causes progressive damage and potentially life-threatening problems. Fabry disease is a multisystemic disorder characterised by pain in the extremities in the teens, angiokeratoma and in later life, renal disease and stroke There is a broad spectrum of disease severity, both cardiac and renal variants have been described. Due to X-linked recessive inheritance, males are more often affected with Fabry disease than females. However, females who are carriers for the disorder may have physical findings ranging from asymptomatic to severe and may depend in part on the randomness of X-inactivation and occasionally skewed X-inactivation. Mutations in the GLA gene , located on Chromosome Xq22 ,are responsible for the enzyme deficiency and subsequent development of Fabry Disease .

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Fanconi Anaemia

Introduction

Fanconi anaemia is a rare chromosomal breakage syndrome which has a prevalence of approximately 1 in 350,000. There is a high variability in the phenotype which is dependant on the patient’s complementation group (see below). The main features include pre- and postnatal growth delay; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); a typical facial appearance with small head, eyes, and mouth; hearing loss; hypogonadism and reduced fertility; cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); progressive aplastic anemia, pancytopenia, bone marrow failure; and an increased risk of cancer (especially acute myeloid leukemia). Cultured FA cells are unusually sensitive to DNA crosslinking agents such as mitomycin C whereas their sensitivity to radiation is close to normal. Fanconi anaemia is caused by a homozygous or compound heterozygous mutation in a FANC gene. There are at least 15 different genetic subtypes (complementation groups) that can lead to the Fanconi anaemia phenotype (FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N, O and P). The FANCD1 gene is also known as BRCA2 (13q12-13). The most common cause of Fanconi anaemia (in 66% of patients) is mutation of the FANCA gene (16q24.3). Approximately 12% of FA patients are in the FANCC complementation group (9q22.3) and 12% in the FANCG group (9p13). The FANC proteins are part of the complex FANC/BRCA pathway involved in the cellular response to and repair of DNA damage. Fanconi anaemia is an autosomal recessive inherited disorder, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

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Fluorescence in situ hybridisation

Introduction

Fluorescence in situ hybridisation (FISH) is a molecular cytogenetic technique which detects the presence of specific DNA sequences at a resolution that is greater than conventional chromosome analysis. The FISH test only looks at a specific region of the chromosome(s) in question and is not a whole genome screen - this is done using microarray (aCGH) testing. FISH can be used to detect loss and gain or rearrangements of genetic material of variable size, from a single gene to a whole chromosome.

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Fragile X Syndrome

Introduction

FragileX is an X-linked dominant syndrome characterised by learning difficulty, delayed developmental milestones, behavioural difficulties and unusual cranio-facies. The mutation responsible for >99% of cases is an expansion of a (CGG)n repeat within the FMR-1 gene. Expansions above a critical size lead to DNA hyper-methylation and silencing of the gene.

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Fragile X Tremor/Ataxia Syndrome (FXTAS)

Introduction

Fragile X Tremor/Ataxia Syndrome (FXTAS) is a late onset neurodegenerative disorder, whose major clinical manifestations include progressive intentional tremor, ataxia and Parkinsonism. The pathogenic mutation is an expansion (Premutation) in a CGG repeat tract within the FMR1 gene. Expansion of this repeat region, (between approximately 59-200 repeats) leads to increased transcription and a proposed toxic gain of function of FMR1 RNA. (see also “Fragile X Syndrome” and “POF1” service profiles)

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Fragile-X Associated Premature Ovarian Insufficiency (FXPOI)

Introduction

Premature ovarian insufficiency is a heterogeneous disorder characterised by menopause before the age of 40 years. Up to 20% of female carriers of an FMR1 “Premutation” (expansion of a CGG repeat tract in within the FMR1 gene, between approximately 59-200 repeats) develop premature ovarian insufficiency, and this form of the condition has been classified as FXPOI. The relationship between the premutation size and risk of developing FXPOI is not linear, with maximum risk confined to carriers with an expansion of 80-100 repeats (Ennis et al 2006). The molecular basis of FXPOI is unknown. (see also “Fragile X Syndrome” and “FXTAS” service profiles)

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Gaucher Disease

Introduction

Gaucher disease is an autosomal recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. This deficiency results in the accumulation of glucocerebroside. Gaucher disease is a multisystemic disorder characterised by haematological problems, hepatosplenomegaly, and skeletal disease and, in more severe forms, neurological deterioration. There is a broad spectrum of disease severity but this can be divided into 3 disease sub-types according to disease symptoms. • Non-neuronopathic (Type I) Gaucher Disease – characterised by anaemia, hepatosplenomegaly and bone disease but without neurological symptoms. • Acute neuronopathic (Type II) Gaucher Disease – these patients show profound brain impairment and usually die before the age of 2 years. • Chronic neuronopathic (Type III) Gaucher disease – characterised by anaemia, massive hepatosplenomegaly, bone disease and neurological symptoms such as horizontal supranuclear gaze palsy. Gaucher disease is caused by mutations in the GBA gene, which encodes for the enzyme glucocerebrosidase. The gene is situated on chromosome 1 and contains thirteen exons .A number of common mutations exist, particularly in the Ashkenazi Jewish population, but many are unique to the family and include a variety of point mutations, deletions, and splice junction defects. There is a highly homologous pseudogene which is situated 16Kb downstream from the functional gene. Rearrangements between the fuctional and the pseudogene can also introduce mutations.

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Huntington Disease

Introduction

Huntington Disease is an autosomal dominant disorder of the CNS, characterised by involuntary movements, impaired motor co-ordination and dementia. Variant alleles of 36 or more repeats in a polymorphic (CAG)n tract in the Huntingtin gene on chromosome 4p16.3 are pathogenic.

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Hypertrophic Cardiomyopathy (HCM)

Introduction

We simultaneously sequence 22 genes known to cause inherited hypertophic cardiomyopathy. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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I cell disease

Introduction

I-cell disease (also called mucolipidosis II a/ß, ML-IIa/ß) is an autosomal recessive disorder caused by a deficiency of the membrane bound enzyme UDP-N –acetylglucosamine- 1-phosphotransferase. The GNPTAB gene encodes two out of three subunits of the enzyme , a heterohexameric complex of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene .In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for endocytosis of lysosomal enzymes into the lysosome Deficiency of N –acetylglucosamine- 1-phosphotransferase prevents appropriate trafficking of lysosomal enzymes and thus preventing normal processing. One unique feature of this disease was the presence of phase-dense intracytoplasmic inclusions in the fibroblasts of patients. These cells were termed inclusion cells, or I-cells; thus, the disease was designated I-cell disease. Individuals with more severe features have ML II; those with less severe, or attenuated, features have ML III. I-cell disease is characterized by severe psychomotor retardation that rapidly progresses leading to death between 5 and 8 years of age. Although there are similar signs and symptoms, the earlier onset of symptoms and the lack of mucopolysacchariduria distinguish I-cell disease from Hurler syndrome. The GNPTAB gene is located on chromosome 12q23.3 and encodes a 1256 amino acid precursor protein

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ICF Syndrome

Introduction

Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare chromosomal breakage syndrome which has a prevalence of less than 1 in 1,000,000 (approximately 50 affected individuals have been reported). The main features of ICF syndrome are immunodeficiency, mild facial dysmorphism, growth delay, failure to thrive, and psychomotor development and speech delay. Facial features include hypertelorism, flat nasal bridge, low-set ears, and protrusion of the tongue, epicanthic folds, and micrognathia. ICF syndrome is caused by a mutation in the DNMT3B gene which is a DNA methyltransferase gene on chromosome 20 at 20q11.2. The DNMT3B protein is required for genome wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. ICF syndrome is an autosomal recessive inherited disorder, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

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Kabuki Syndrome

Introduction

Kabuki syndrome is a dominantly inherited congenital mental retardation syndrome with additional features including postnatal dwarfism, unusual facies characterised by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy. The majority of Kabuki syndrome cases are caused by mutations in the MLL2 gene (also known as KMT2D) located on chromosome 12q13.12. Mutations have also been reported in the KDM6A gene on Xp11.3. Most Kabuki syndrome cases occur de novo.

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Kallmann Syndrome

Introduction

Kallmann syndrome is more common in males than females with an approximate incidence of 1 in 8,000 males compared to 1 in 40,000 females. The X-linked form of Kallmann syndrome is caused by a mutation in or deletion of the KAL1 gene on chromosome Xp22.3. It is a developmental disorder where males with show anosmia (an absent or reduced sense of smell) and hypogonadotropic hypogonadism. Female carriers have partial or complete anosmia. Males with hypogonadotropic hypogonadism are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males. Affected females usually do not begin menstruating at puberty and have little or no breast development.

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Klinefelter Syndrome

Introduction

Klinefelter syndrome has a prevalence of approximately 1 in 500 males. It results from the gain of an additional X chromosome in each cell, giving a 47,XXY male karyotype. The features are mild, children may present with small testes, small penis, hypospadias or cryptorchidism (undescended testes). They may have learning disabilities and difficulty with speech and language development. At puberty boys with Klinefleter syndrome can develop breast enlargement (gynecomastia), have reduced facial and body hair, tall stature and hypogonadism. Individuals with Klinefelter syndrome are invariably infertile. Klinefelter syndrome cases arise as a sporadic event. However, 46,XX males have also been described with features of Klinefelter syndrome. In this case the syndrome results from the translocation of Y material (including the sex determining region, SRY) to the X chromosome during paternal meiosis. Klinefelter syndrome can also appear in a mosaic form, where normal cells are also present in the individual (a 47,XXY/46,XY karyotype). These individuals may exhibit a milder phenotype, which is dependant on the extent and tissue distribution of the normal cell line.

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Krabbe Disease

Introduction

Krabbe Disease is an autosomal recessive inherited disorder affecting myelin in the peripheral and central nervous system. Although the most common form of the disease is the classic fatal severe infantile form (classic Krabbe disease), later onset forms have also been described and up patients up to 50 years have been diagnosed.All patients are deficient in galactocerebrosidase,(GALC) the lysosomal enzyme responsible for the hydrolysis of important glycolipids Assays of GALC activity in leukocytes or cultured fibroblasts with use of appropriate natural glycolipid substrates can establish a diagnosis. . One mutation a 30kb deletion makes up over 50% of mutant alleles in patients from most of northern Europe

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LCHAD Deficiency

Introduction

Defects in Trifunctional enzyme subunit alpha (HADHA gene) are the cause of long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the Trifunctional protein complex are normal or only slightly reduced.There is considerable heterogeneity in LCHAD deficiency, including fulminant hepatic disease, hypertrophic cardiomyopathy and in some patients unusual features such as progressive neuropathy and pigmentary retinopathy. Most patients with LCHAD deficiency present with signs of fasting induced hypoketotic hypoglycemia.During pregnancy, mothers of affected infants can develop acute fatty liver of pregnancy or hypertension, elevated liver enzymes and low platelets (HELLP) syndrome.The common missense mutation c.1528G>C in LCHAD deficiency accounts for 87% of mutant alleles in patients with LCHAD.

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Leber Hereditary Optic Neuropathy

Introduction

Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless, subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected .LHON is attributed to mutations in the mitochondrial DNA (mtDNA)genes encoding subunits of complex 1 NADH dehydrogenase. There are three primary mutations m.11778G>A (MT-ND4) , m.14484T>C (MT-ND6) and m.3460G>A (MT-ND1) accounting for >90% of cases of LHON.

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Long QT Syndrome (LQT)

Introduction

We simultaneously sequence 12 genes known to cause inherited long QT syndrome. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Medium Chain Acyl-CoA Dehydrogenase Deficiency MCADD

Introduction

MCAD deficiency (a fatty acid oxidation defect) is the most common defect in the pathway of mitochondrial beta-oxidation.The most frequent presentation is episodic hypoketotic hypoglycemia provoked by fasting and beginning in the first 2 years of life. Accumulation of fatty acid intermediates results in plasma and urinary metabolites, some of which are general indicators of impaired function of the Beta -oxidation pathway (e.g. dicarboxylic acids), while others are unique and characteristic of MCAD deficiency Patients with MCAD deficiency can appear normal, but in some cases, the first episode is fatal and can resemble sudden infant death syndrome (SIDS) .Diagnosis can be made by analysis of plasma acylcarnitines or urinary acylglycines or by molecular analysis.The common mutation c.985A>G accounts for >87% of mutant alleles in Europeans.

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Miller-Dieker Lissencephaly Syndrome

Introduction

Miller-Dieker syndrome (MDS) has a prevalence of approximately 1 - 9 in 1,000,000. It is caused by a deletion of chromosome 17p13.3. It is characterised by classical lissencephaly and distinct facial features including a prominent forehead, bi-temporal narrowing, depressed nasal bridge, anteverted nares, mid-face hypoplasia, and a thin upper lip. Children with MDS present with microcephaly, growth deficiency, neonatal jaundice, severe developmental delay, they usually have epilepsy, and feeding problems are common. The majority of cases arise as a new deletion but in approximately 12% of cases the deletion is the result of a derivative or recombinant chromosome 17 inherited from a parent who carries a balanced chromosome rearrangement.

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Mitochondrial DNA

Introduction

Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). Some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON] see entry for LHON), but many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many affected individuals display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category. Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus.

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MLH1 Promoter Hypermethylation

Introduction

MLH1 loss determined by IHC is observed in dMMR tumours from both Lynch syndrome patients but also a significant minority of sporadic tumours. MLH1 promoter hypermethylation is a common somatic epimutation in sporadic tumours yet is rare in Lynch syndrome tumours where the 'first hit' is inherited. MLH1 promoter hypermethylation can be used to stratify Lynch syndrome risks in patients particularly those which meet revised Bethesda criteria.

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Molecular Autopsy

Introduction

We simultaneously sequence 56 genes known to cause inherited sudden unexplained cardiac death. We provide a comprehensive scientific interpretation of variants found and issue a report summarising our findings.

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Mucopolysaccharidosis II

Introduction

MPS II (Hunter Syndrome OMIM 309900) is an X-linked recessive mucopolysaccharide storage disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulphatase. This deficiency results in the accumulation of heparan and dermatan sulphates. MPS II is a multisystemic disorder characterised by facial dysmorphism, dysostosis multiplex and neurological deterioration. Death usually occurs during the second decade. Milder forms of the disorder show slower progression of somatic features and absence of neurological problems. The classification into mild and severe forms is somewhat artificial as the disorder exhibits a wide spectrum of clinical severity, defined by the underlying genetic lesion. The iduronate sulphatase gene (IDS) is stuated on the X chromosome at Xq28 spanning 24 kb and encompassing 9 exons that encode a preproprotein of 550 amino acids.

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Mucopolysaccharidosis IIIa

Introduction

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive mucopolysaccharide storage disorder caused by a deficiency of various lysosomal enzymes. MPS III encompasses a group of four lysosomal storage disorders resulting from a failure to break down the glycosaminoglycan heparan sulphate. Each of the four sub-types (A, B, C, & D) of MPS III is caused by the deficiency of a different enzyme in the degradative pathway of heparan sulphate. MPS IIIA (Sanfilippo A Syndrome OMIM 252900) is caused by a deficiency of the enzyme heparan-N-sulphatase (Sulphamidase), which results in the accumulation of heparan sulphates in the lysosome. MPS IIIA is a multisystemic disorder, clinical symptoms of which usually occur after about 2 years of apparently normal development. These symptoms include hyperactivity, aggressive behaviour, delayed speech development, sleep disturbances, coarse hair, hirsutism and diarrhoea which are then followed by progressive mental retardation around 6 to 10 years of age resulting in death usually between the second and third decade of life. Type A has been reported to be the most severe, with earlier onset and rapid progression of symptoms and shorter survival. The gene for sulphamidase or N-sulphoglucosamine sulphohydrolase (gene symbol SGSH) resides on chromosome 17q25.3 spanning 11 kb and comprising 8 exons encoding a 502 amino acid precursor protein that is processed to a 482 amino acid glycoprotein that is active as a homodimer.

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Mucopolysaccharidosis IIIb

Introduction

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive mucopolysaccharide storage disorder caused by a deficiency of various lysosomal enzymes. MPS III encompasses a group of four lysosomal storage disorders resulting from a failure to break down the glycosaminoglycan heparan sulphate. Each of the four sub-types (A, B, C, & D) of MPS III is caused by the deficiency of a different enzyme in the degradative pathway of heparan sulphate. MPS IIIB (Sanfilippo B Syndrome) is caused by a deficiency of the enzyme alpha-N-acetylglucosaminidase (glucosaminidase), which results in the accumulation of heparan sulphates in the lysosome. MPS IIIB is a multisystemic disorder, clinical symptoms of which usually occur after about 2 years of apparently normal development. These symptoms include hyperactivity, aggressive behaviour, delayed speech development, sleep disturbances, coarse hair, hirsutism and diarrhoea which are then followed by progressive mental retardation resulting in death usually between the second and third decade of life. The gene for glucosaminidase or alpha-N-acetylglucosaminidase (gene symbol NAGLU) resides chromosome17q21 spanning 8.3 kp and comprising 6 exons that encode a 743 amino acid precursor protein that is processed to a 720 amino acid glycoprotein.

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Mucopolysaccharidosis IVa

Introduction

MPS IVA Morquio disease (OMIM 253000) is an autosomal recessively inherited mucopolysaccharide storage disorder caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulphatase (GALNS, galactose-6-sulphate sulphatase) resulting in the accumulation of keratan sulphate and chondroitin-6-sulphate mainly in the cornea and cartilage, leading to distinguishing skeletal abnormalities. MPS IVA is a multisystemic disorder with clinical symptoms covering a wide spectrum of characteristics and is distinguished from other MPS by a spondyloepiphyseal dysplasia and normal intelligence. In the classical and most severeform, symptoms begin between 1-4 years of age and include tendency to fall, coarse features, dwarfism with short trunk, osteoporosis, corneal deposits, hearing impairment, and hepatomegaly. A milder form of MPS IVA is characterized by mild bone and somatic involvement with survival to 60 years of age and normal quality of life The gene for GALNS is located on chromosome 16q24.3 and has 14 exons. The GALNS cDNA has an open reading frame of 1566 bp which encodes a 522 amino acid protein.

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Mucupolysaccharidosis I

Introduction

MPS I (Hurler Syndrome) is an autosomal recessive mucopolysaccharide storage disorder caused by a deficiency of the lysosomal enzyme alpha-iduronidase. . There is a broad spectrum of disease severity, The disorder is divided into 3 disease sub-types according to disease symptoms. • Hurler Disease –Severe Hurler/Scheie – mild CNS involvement Scheie Disease – characterised by CNS involvement being absent MPS I is caused by mutations in the IDUA gene, which contains fourteen exons

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Niemann Pick Disease Type C1 and C2

Introduction

Niemann-Pick Disease type C (NPC) is a rare autosomal recessive neurodegenerative disorder resulting from mutations in one of two genes (NPC1 or NPC2). It is characterised by intracellular accumulation of unesterified cholesterol and glycosphingolipids (in the brain) within the late endosomes-lysosomes. NPC is clinically heterogenous with a broad spectrum of phenotypes and the age of onset ranges from perinatal through to adulthood Common symptoms include hepatomegaly, splenomegaly, jaundice, vertical supranuclear gaze palsy (VSGP), The NPC1 gene accounts for 95% of NPC patients and codes for a 1278 amino acid transmembrane glycoprotein, that regulates cholesterol transport from the late endosome-lysosomes to other intracellular compartments. The NPC2 gene accounts for ~4% of NPC patients and codes for a 151 amino acid (5 Exons) soluble ubiquitiously expressed lysosomal glycoprotein involved in lysosomal sterol transport. Most cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. Theoretically NPC2 disease is treatable by bone marrow transplantation (BMT). Referrals – We accept referrals for mutation scanning of both genes to confirm a clinical or biochemical diagnosis. We can also offer carrier testing to family members.accounts for 5% of NPC patients, which codes for a 151 amino acid (5 Exons) soluble ubiquitiously expressed lysosomal glycoprotein involved in lysosomal sterol transport. Most cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. Theoretically the disease is treatable by bone marrow transplantation (BMT), as the NPC2 protein is small, soluble and secreted and recaptured by the mannose-6-phosphate pathway.throughout 25 exons, conversely a large percentage are found within the cysteine-rich loop (Exons 18-23).

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Non-Invasive Fetal Sex Determination

Introduction

Knowledge of the sex of a fetus is important where there is a risk of an X-linked genetic disorder or in cases where intrauterine treatment is dependent on the sex of the fetus e.g. Congenital Adrenal Hyperplasia. Fetal sex can be determined by monitoring cell free fetal DNA (ffDNA) extracted from maternal plasma for the presence or absence of Y chromosome sequences.

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Pallister-Killian Syndrome

Introduction

Pallister-Killian syndrome (PKS) has a prevalence of approximately 1 in 25,000. It is a dysmorphic condition caused by mosaic tissue-limited tetrasomy of chromosome 12p. This is seen as an additional small metacentric isochromosome i(12)(p10). A proportion of fibroblasts (30-100%) will have tetrasomy 12p; however the karyotype of lymphocytes is normal. The main features include profound intellectual deficiency, seizures and streaks of skin hypo- or hyper-pigmentation. Facial features include a prominent forehead with sparse anterior scalp hair, sparse eyebrows and lashes, flattening of the head, wide-set eyes, short nose with anteverted nostrils, flat nasal bridge, a large mouth with downturned corners and a prominent upper lip, a protruding tongue and a short neck. Prenatal diagnosis may be possible through ultrasound scan findings such as diaphragmatic hernia, polyhydramnios, fetal hydrops, cardiac malformations, and short limbs. All reported cases of Pallister-Killian syndrome have arisen sporadically.

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Patau Syndrome

Introduction

Patau Syndrome (trisomy 13) occurs in approximately 1 in 16000 live births. It is caused by an additional chromosome 13 or extra chromosome 13 material. The features commonly associated with trisomy 13 include a number of midline defects such as cleft lip and palate, holoprosencephaly, microphthalmia and hypertelorism, (small, wide-spaced eyes) and microcephaly (small head). Also common are extra fingers and/or toes, hypotonia, heart, brain, and spinal cord abnormalities. Approximately 80% of infants born with trisomy 13 do not survive the first month of life. The majority of cases are "free" trisomy 13, but in approximately 20% of cases the additional chromosome 13 material is derived from a translocation, which may or may not be inherited from a parent. Although free trisomy 13 occurs sporadically, there is an increased risk of a Patau syndrome pregnancy with increasing maternal age. Trisomy 13 may also appear in a mosaic form, where normal cells are also present in the individual. These individuals may exhibit a milder phenotype, which is dependant on the extent and tissue distribution of the normal cell line.

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Pitt Hopkins Syndrome (TCF4)

Introduction

Pitt-Hopkins syndrome is a rare neurodevelopmental disorder characterized by severe learning disability, dysmorphic facial features, seizures and breathing problems and usually occurs sporadically. There is a considerable degree of clinical overlap with the more common Angelman syndrome. Pitt-Hopkins syndrome can be caused by heterozygous mutations in the Transcription Factor 4 gene (TCF4) located on chromosome 18q21.1.

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Prader Willi Syndrome

Introduction

PWS is sporadic in occurrence, with a reported rate of prevalence from 1/10,000 to 1/30,000. Severe hypotonia and feeding difficulties in early infancy, followed by excessive eating, morbid obesity and learning difficulties characterise the syndrome. PWS arises from paternal deletion of 15q11-13 on chromosome 15 (70% of cases) or maternal uniparental disomy (30%).

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Prenatal - Abnormal Ultrasound Scan Findings

Introduction

The NHS fetal anomaly screening programme (FASP) provides screening for fetal anomalies to all pregnant women in the UK. This includes an ultrasound scan as part of the Combined test between 10 and 14 weeks gestation, measuring fetal nuchal translucency, and a fetal anomaly scan between 18 and 20 weeks gestation. Where nuchal translucency measurements are above 3.5mm in the first trimester or 6mm in the second trimester or other fetal structural or growth abnormalities are identified by scan, women are offered an invasive prenatal diagnostic test. This laboratory will carry out an initial rapid Quantitative–Fluorescent PCR (QF-PCR) test on the sample to exclude trisomy 13, 18 and 21 (Patau, Edwards and Down syndromes respectively), triploidy, and Turner syndrome where there is a raised nuchal translucency or other clinical indication. G-banded chromosome analysis is performed where aneuploidy is identified to confirm the finding and give an indication of the risk of recurrence in future pregnancies. Samples that show a normal result by QF-PCR will be tested by microarray analysis to look for genomic imbalances that may explain the cause of fetal abnormalities. Testing may be performed on either chorionic villi (between 11 and 14 weeks gestation) or amniotic fluid (after 15 weeks gestation). QF-PCR results will usually be available via the antenatal clinic within three working days and microarray or chromosome analysis results within fourteen calendar days.

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Prenatal - Increased Risk of Down Syndrome Following Screening

Introduction

The NHS fetal anomaly screening programme (FASP) provides screening for fetal anomalies as well as Down, Edwards and Patau syndromes to all pregnant women in the UK. Women are offered the Combined test between 10 and 14 weeks gestation which measures fetal nuchal translucency by ultrasound scan and pregnancy associated proteins in maternal blood serum. Patients presenting later in pregnancy are offered the Quadruple test measuring maternal serum only. The screening test gives a risk of the pregnancy being affected with Down, Edwards or Patau syndromes. Where this risk is high (greater than 1 in 150), an invasive prenatal diagnostic test is offered. This involves either chorionic villus sampling (between 11 and 14 weeks gestation) or an amniocentesis (after 15 weeks gestation). This laboratory will carry out a rapid Quantitative–Fluorescent PCR (QF-PCR) test on the sample to diagnose or exclude trisomy 13, 18 and 21 (Patau, Edwards and Down syndrome respectively). Results will usually be available via the antenatal clinic within three working days. Chromosome analysis is performed where trisomy is identified to confirm the finding and give an indication of the risk of recurrence in future pregnancies.

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Pseudoachondroplasia

Introduction

Pseudoachondroplasia (PSACH) is an autosomal dominant osteochondrodysplasia affecting at least 1 in 20,000 individuals and is characterised by disproportionate short stature, deformity of the legs, short fingers, loose joints and ligamentous laxity. PSACH is caused exclusively by mutations of the cartilage oligomeric matrix protein gene (COMP) located on chromosome 19p13.1.

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Rapid QF-PCR Testing

Introduction

QF-PCR is a rapid molecular test carried out within the Cytogenetics Department for testing for aneuploidy, specifically chromosomes 13, 18 and 21 and the sex chromosomes.

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Rare Disease Service

Introduction

The Rare Disease service confirms mutations found in research laboratories and tests for these mutations within the extended family. Testing for unidentified mutations (mutation scanning) falls outside the scope of the service, even if these are recurrent.

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RAS-MAPK Pathway Syndromes

Introduction

The RAS-MAPK pathway is essential for regulation of the cell cycle, cell differentiation, proliferation and cell senescence. Dysregulation of this pathway by germline mutations in various of the genes involved results in a RAS-MAPK pathway syndrome. These syndromes are a group of congenital disorders which share overlapping phenotypic features including cardiomyopathy, dysmorphic facial features and growth/developmental delay. Each syndrome also has its own distinct features. We offer molecular genetic testing for: CFC syndrome (BRAF, KRAS, MAP2K1/MEK1 and MAP2K2/MEK2) Costello syndrome (HRAS) SHOC2 c.4A>G p.(Ser2Gly) (Noonan-like syndrome with loose anagen hair: phenotype may overlap with both Costello and CFC syndrome)

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Recurrent Miscarriage

Introduction

In about 2-5% of couples with a history of recurrent miscarriage, one or the other of the couple carries a balanced chromosome rearrangement which confers an increased risk of miscarriage or of having live births with an unbalanced chromosome rearrangement. For couples ascertained through recurrent miscarriage, the risk of chromosomally unbalanced pregnancies surviving to term is low and therefore routine karyotyping of these couples is not indicated.

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Roberts Syndrome

Introduction

Roberts syndrome (RBS) is a rare chromosomal breakage syndrome which has a prevalence of less than 1 in 1,000,000 (approximately 150 affected individuals have been reported). The main features of Roberts syndrome include pre- and postnatal growth delay, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit. The upper limbs are more frequently and severely affected than lower limbs with the radius being the most affected in the upper limbs, and the fibula in the lower limbs. Aplastic or hypoplastic thumbs, oligodactyly, clinodactyly or syndactyly can also occur. Facial features include microcephaly (more severe in males than in females), a beaked nose with small nostrils, wide-set protruding eyes, micrognathia, downslanting palpebral fissures, dysplastic or small ears, cloudy cornea or cataracts, and cleft lip and palate. Roberts syndrome is caused by a mutation in the ESCO2 gene which is found on chromosome 8 at 8p21.1. The protein is an acetyltransferase required for the establishment of sister chromatid cohesion at the centromere during S phase. ESCO2 gene mutations lead to delayed cell division, increased cell death and impaired cell proliferation with random chromosome loss or gain. Roberts syndrome is an autosomal recessive inherited disorder, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

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SHOX Deletion

Introduction

Short stature homeobox (SHOX) deletions and mutations are associated with idiopathic short stature. One copy of the SHOX gene is located on each of the sex chromosomes (the X and Y chromosomes) in an area called the pseudoautosomal region. Therefore, both males and females have two functional copies of the SHOX gene in each cell. The loss of one functional copy of the SHOX gene in patients with Turner syndrome is thought to be at least partly responsible for short stature and skeletal abnormalities (such as unusual rotation of the wrist and elbow joints) in women with this condition. Changes involving the SHOX gene are also responsible for several skeletal disorders characterized by short stature such as Leri-Weill Dyschondrosteosis and Langer Mesomelic Dysplasia (a more severe form of Leri-Weill Dyscondrosteosis). The majority of cases arise as a new deletion but in some cases the deletion is the result of a derivative or recombinant sex chromosome inherited from a parent (usually their mother) who carries a balanced chromosome rearrangement.

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Shwachman-Diamond Syndrome

Introduction

SDS is an autosomal recessive disorder with clinical diagnosis relying on evidence of exocrine pancreatic dysfunction and bone marrow failure with single- or multi-lineage cytopenia. Other primary features used in support of the diagnosis include short stature, skeletal abnormalities and hepatomegaly. SBDS, on chromosome 7q11, is the only gene presently known to be associated with SDS. Fewer than 10% of individuals with clear clinical indications of SDS do not appear to have mutations in SBDS,

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Smith-Magenis Syndrome

Introduction

Smith-Magenis syndrome (SMS) has a prevalence of approximately 1 in 15,000 to 25,000. It is caused by a 3.7 Mb interstitial deletion which includes the gene RAI1 at 17p11.2. Approximately 10% of cases are the result of a mutation of the RAI1 gene which gives rise to a milder phenotype. The main characteristics of Smith-Magenis syndrome include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and distinctive behavioural problems. Facial features include a broad, square-shaped face with a depressed nasal bridge, deep-set eyes, and full cheeks, a prominent lower jaw, and midface hypoplasia. The mouth tends to turn downward with a full, outward-curving upper lip. Affected individuals have a hoarse deep voice and often have dental problems. Most patients have behavioural problems. These include frequent temper tantrums and outbursts, aggression, anxiety, impulsiveness, and difficulty paying attention. Self-injury, including biting, hitting, head banging, and skin picking, is very common. The vast majority of cases arise as a new deletion.

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Sotos Syndrome

Introduction

Sotos syndrome has a prevalence of less than 1 in 1,000,000. Mutations and deletions of the NSD1 gene at chromosome 5q35 are responsible for more than 75% of cases of Sotos syndrome. The main features are excessively rapid growth, acromegalic features, cerebral gigantism and macrocephaly, developmental delay, hypotonia, advanced bone age and scoliosis. Facial features include a long, narrow face, a high forehead, down-slanting palpebral fissures, flushed cheeks and a small, pointed chin. The majority of cases (95%) arise as a new mutation or deletion. The remaining 5% are familial mutations or deletions.

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SRY deletions

Introduction

Deletions and mutations of the sex-determining region Y (SRY) gene on the Y chromosome at Yp11.3 are associated with a number of disorders of sexual development (DSD), which range from complete sex reversal to incomplete masculinisation. These include 46,XY gonadal dysgenesis (including Swyer syndrome), 46,XY DSD, ovotesticular DSD, 46,XX DSD and 45,X/46,XY mixed gonadal dysgenesis. Deletions of SRY can occur as interstitial or terminal deletions or as structural rearrangements such as an isodicentric or dicentric Y chromosome with two copies of the long arm. The DSD’s can occur as complete loss of a Y chromosome in a mosaic karyotypes such as 46,XX/46,XY or 45,X/46,XY. Individuals with mosaic karyotypes will have a variable phenotype, which is dependent on the extent and tissue distribution of the different cell lines.

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Steroid Sulfatase Deficiency

Introduction

Steroid Sulfatase (STS) deficiency is the cause of X-linked Icthyosis. Approximately 90% of patients with X-linked Icthyosis have a deletion or mutation of the STS gene at Xp22.3. Males are more likely to be affected than females, although female patients with STS have been reported in the literature. Females are usually unaffected carriers of the STS deletion or mutation. Onset usually occurs in the neonatal period and is seen as mild erythroderma and generalized exfoliation of the skin. Affected boys later develop large, polygonal, dark brown scales, especially on the neck, extremities, trunk, and buttocks. Some patients with larger deletions may also present with Kallmann syndrome, mental retardation and short stature, depending on the size of the deletion.

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Triple X Syndrome

Introduction

Triple X syndrome (XXX or trisomy X) occurs in approximately 1 in 1000 females. The triple X syndrome results from the gain of an additional X chromosome in each cell, giving a 47,XXX female karyotype. Triple X females are only mildly affected or asymptomatic, and the majority of cases escape clinical notice or are detected as incidental findings. Triple X syndrome features include hypotonia, epicanthic folds, mild developmental problems (in some cases) and tall stature. Although fertility is considered to be normal in triple X females, they are at an increased risk of premature ovarian failure. Triple X syndrome arises as a sporadic event but can also appear in a mosaic form, where normal cells are also present in the individual (a 47,XXX/46,XX karyotype). These individuals may exhibit a milder phenotype, which is dependant on the extent and tissue distribution of the normal cell line.

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Turner Syndrome

Introduction

Turner syndrome has a prevalence of approximately 1 in 2500 female births. In 50% of cases the syndrome results from the complete loss of one X chromosome in a female (a 45,X karyotype). Prenatally, Turner syndrome may present as cystic hygroma or fetal hydrops detected by ultrasound scan. Postnatally, the most common feature of Turner syndrome is short stature, which becomes evident by about age 5. The other main features include extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, puffiness or swelling (lymphoedema) of the hands and feet, heart problems, skeletal abnormalities, and/or kidney problems. Many affected girls do not undergo puberty unless they are treated with the hormone oestrogen. The majority of individuals with Turner syndrome are infertile, however, small percentage of females with Turner syndrome retain normal ovarian function through young adulthood. The majority of females with Turner syndrome have normal intelligence. Some Turner syndrome patients may have a cell line containing Y chromosome material which is associated with an increased risk of gonadoblastoma. In the majority of cases Turner syndrome arises as a sporadic event. Variant Turner syndrome can also occur when one normal X chromosome and one structurally abnormal X chromosome are present. Individuals with variant Turner syndrome may present with a milder phenotype than those females where a complete X chromosome is missing. Turner syndrome can also appear in a mosaic form, where normal cells are also present in the individual (a 45,X/46,XX karyotype). These individuals may exhibit a milder phenotype, which is dependent on the extent and tissue distribution of the normal cell line. One of the critical regions for the Turner syndrome phenotype, specifically short stature and skeletal abnormalities, is loss of the SHOX gene at Xp22.33.

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Williams-Beuren Syndrome

Introduction

7q11.23 deletion syndrome, more commonly known as Williams syndrome (WS) or Williams-Beuren syndrome, has a prevalence of approximately 1 in 20,000. It is a contiguous gene syndrome caused by a microdeletion of 1.5 to 1.8 Mb at 7q11.23. The deleted region includes approximately 28 genes, including CLIP2, ELN, GTF2I, GTF2IRD1, and LIMK1. The deletion causes a broad spectrum of clinical features. The main characteristics of Williams-Beuren syndrome are mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features and heart and blood vessel (cardiovascular) problems (supravalvular aortic stenosis). Infants often present with hypercalcemia. The characteristic "elfin" facial features include a broad forehead, a short nose with a flattened nasal bridge and a broad, bulbous tip, full cheeks, a wide mouth with full lips, dental problems, periorbital oedema, epicanthus and often stellar iris. With age, the face becomes narrower with coarser features. Individuals with Williams-Beuren syndrome have visual-spatial deficits (which cause difficulty with drawing and assembling puzzles) but tend to have good language and musical skills. They can display hypersocial behaviour and interact well with other people but also have a distinctive sensitivity to noise. The vast majority of cases arise as a new deletion. Approximately 95% of patients have a deletion of the ELN gene.

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Wolf-Hirschhorn Syndrome

Introduction

Wolf-Hirschhorn syndrome (WHS), also known as 4p16.3 deletion syndrome, has a prevalence of approximately 1 in 50,000. It is associated with a deletion of chromosome 4p16.3. The syndrome is also referred to as Pitt syndrome or Pitt-Rodgers-Dank syndrome. Characteristic features of WHS include distinctive craniofacial features, pre- and postnatal growth deficiency, mild to severe intellectual disability, seizures, congenital heart defects and genital and renal anomalies. The craniofacial features include a broad and/or beaked nose, high forehead ("Greek warrior helmet" appearance), prominent glabella, hypertelorism, high-arched eyebrows, microcephaly, coloboma of the eye, widely-spaced and protruding eyes, epicanthal folds, short philtrum, cleft lip or palate, distinct mouth with downturned corners, micrognathia, and dysplastic ears with preauricular tags. The majority of cases arise as a new deletion but in approximately 5-13% of cases the deletion is the result of a derivative or recombinant chromosome 4 inherited from a parent who carries a balanced chromosome rearrangement. There is known recurrent cryptic reciprocal translocation t(4;8)(p16;p23), which confers a greater risk of WHS.

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X-linked Hydrocephalus

Introduction

X-linked hydrocephalus is the most common form of inherited hydrocephalus accounting for 2-7% of cases of primary congenital hydrocephalus. Mutations in the gene encoding the L1 neural cell adhesion molecule (L1-CAM) have been shown to result in X-linked hydrocephalus in both familial and sporadic cases. In addition, mutations in this same gene have been shown to be responsible for cases of MASA syndrome and a proportion of familial spastic paraplegia.

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XYY Male

Introduction

The XYY karytotype occurs in approximately 1 in 1000 males. The XYY syndrome results from the gain of an additional Y chromosome in each cell, giving a 47,XYY karyotype. XYY males are mostly asymptomatic or only mildly affected, and the majority of cases escape clinical notice or are detected as incidental findings. The features of XYY syndrome include mild developmental problems (in some cases) and tall stature. Fertility is considered to be normal in XYY males. The XYY karyotype arises as a sporadic event but can also appear in a mosaic form, where normal cells are also present in the individual (a 47,XXY/46,XY karyotype).

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Clinical Indications

Prenatal - Abnormal Ultrasound Scan Findings

Introduction

The NHS fetal anomaly screening programme (FASP) provides screening for fetal anomalies to all pregnant women in the UK. This includes an ultrasound scan as part of the Combined test between 10 and 14 weeks gestation, measuring fetal nuchal translucency, and a fetal anomaly scan between 18 and 20 weeks gestation. Where nuchal translucency measurements are above 3.5mm in the first trimester or 6mm in the second trimester or other fetal structural or growth abnormalities are identified by scan, women are offered an invasive prenatal diagnostic test. This laboratory will carry out an initial rapid Quantitative–Fluorescent PCR (QF-PCR) test on the sample to exclude trisomy 13, 18 and 21 (Patau, Edwards and Down syndromes respectively), triploidy, and Turner syndrome where there is a raised nuchal translucency or other clinical indication. G-banded chromosome analysis is performed where aneuploidy is identified to confirm the finding and give an indication of the risk of recurrence in future pregnancies. Samples that show a normal result by QF-PCR will be tested by microarray analysis to look for genomic imbalances that may explain the cause of fetal abnormalities. Testing may be performed on either chorionic villi (between 11 and 14 weeks gestation) or amniotic fluid (after 15 weeks gestation). QF-PCR results will usually be available via the antenatal clinic within three working days and microarray or chromosome analysis results within fourteen calendar days.

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Prenatal - Increased Risk of Down Syndrome Following Screening

Introduction

The NHS fetal anomaly screening programme (FASP) provides screening for fetal anomalies as well as Down, Edwards and Patau syndromes to all pregnant women in the UK. Women are offered the Combined test between 10 and 14 weeks gestation which measures fetal nuchal translucency by ultrasound scan and pregnancy associated proteins in maternal blood serum. Patients presenting later in pregnancy are offered the Quadruple test measuring maternal serum only. The screening test gives a risk of the pregnancy being affected with Down, Edwards or Patau syndromes. Where this risk is high (greater than 1 in 150), an invasive prenatal diagnostic test is offered. This involves either chorionic villus sampling (between 11 and 14 weeks gestation) or an amniocentesis (after 15 weeks gestation). This laboratory will carry out a rapid Quantitative–Fluorescent PCR (QF-PCR) test on the sample to diagnose or exclude trisomy 13, 18 and 21 (Patau, Edwards and Down syndrome respectively). Results will usually be available via the antenatal clinic within three working days. Chromosome analysis is performed where trisomy is identified to confirm the finding and give an indication of the risk of recurrence in future pregnancies.

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Recurrent Miscarriage

Introduction

In about 2-5% of couples with a history of recurrent miscarriage, one or the other of the couple carries a balanced chromosome rearrangement which confers an increased risk of miscarriage or of having live births with an unbalanced chromosome rearrangement. For couples ascertained through recurrent miscarriage, the risk of chromosomally unbalanced pregnancies surviving to term is low and therefore routine karyotyping of these couples is not indicated.

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