Introduction

22q11.2 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.

Referral information

We accept referrals from patients with appropriate clinical features for a diagnosis of DiGeorge syndrome or from family members of known affected patients.

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Introduction

Angelman syndrome (AS, OMIM ref. 105830) is characterised by severe developmental delay, absent or severely limited speech, gait ataxia and/or tremulousness of the limbs, and a unique behavior with a happy demeanor that includes frequent and sometimes inappropriate laughter, smiling, and excitability. In addition, microcephaly and seizures are common. Affected individuals usually have a characteristic electroencephalography (EEG) appearance with striking high voltage activity. Developmental delay is first noted at around six months of age; however, the unique clinical features of AS may not manifest until after one year of age, and it can take several years before the correct clinical diagnosis is obvious. The diagnosis of AS rests upon a combination of clinical features as well as molecular genetic testing and/or cytogenetic analysis. Consensus clinical diagnostic criteria for AS have been developed. Angelman syndrome (AS) has a prevalence of~1/12,000. Loss of the maternally contributed AS region can occur by five genetic mechanisms: deletion (70-75% of cases), paternal uniparental disomy of chromosome 15 (3-7% of cases), imprinting defects (2-3% of cases), mutation of the ubiquitin-protein ligase (UBE3A) gene (~10% of cases) or unidentified mechanisms (Ramsden et al, 2010, BMC Med. Genet., 11:70).

Referral information

We accept referrals of patients with appropriate signs and symptoms for a differential diagnosis of AS. An expert clinical review is required for referral for UBE3A mutation scanning.

View full test details for Angelman Syndrome (AS)

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 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.

Referral information

Postnatal Referrals

We accept blood samples from babies with ambiguous genitalia, suspected aneuploidies (trisomy 21, trisomy 13 or trisomy 18), for confirmation of a chromosome abnormality detected prenatally or for suspected sex chromosome aneuploidy. We also accept referrals from couples who are undergoing tests for infertility (IVF couples, azoospermic males) and patients with problems of sexual development (suspected Turner syndrome, suspected Klinefelter syndrome, delayed/premature puberty, or premature ovarian failure). We accept referrals for follow-up studies following detection of a chromosome abnormality either in another family member or following a pregnancy loss. We also accept referrals for patients with a family history of a balanced rearrangement (inversion, insertion or translocation). Samples from babies under the age of one month and from pregnant couples are classed as urgent samples (see reporting times).

Prenatal Referrals

We accept chorionic villus and amniotic fluid samples referred for increased nuchal translucency/thickness, increased serum screening risk, increased maternal age, abnormalities seen on ultrasound scan and a family history of balanced rearrangement. Samples will be tested by QF-PCR initially  and will only proceeded to chromosome analysis if an aneuploidy is detected by QF-PCR  We also accept samples referred for a family history of biochemical or molecular disorder; however these are only cultured by the cytogenetics department and the sample/cultured cells forwarded on to the relevant laboratory for specific testing. All prenatal samples are classed as urgent samples.

Solid Tissue Referrals

We accept skin punch biopsy samples from patients referred with suspected mosaicism (e.g. Hypomelanosis of Ito or Pallister-Killian syndrome). We also accept tissue samples from pregnancy loss but these samples are processed by QF-PCR and, where appropriate, by array CGH.  It is essential that the date of delivery is included on all samples from pregnancy loss.

View full test details for Chromosome Analysis

Introduction

Premature ovarian insufficiency is a heterogeneous disorder characterised by menopause before the age of 40 years. Up to 20% of female carriers of a Premutation in the FMR1 gene at Xq27.1 develop premature ovarian insufficiency, and this form of the condition has been classified as Fragile X Associated Primary Ovarian Insufficiency (FXPOI). The relationship between the premutation size and the risk of developing FXPOI is not linear, with maximum risk confined to carriers with an expansion of 80-100 CGG repeats (Ennis et al 2006). The molecular basis of FXPOI is unknown.

Referral information

Testing is used for confirmation of a clinical diagnosis of FXPOI or for exclusion of the diagnosis in patients with relevant clinical indications. Within families with a history of FXPOI, testing is used to confirm a diagnosis or to establish or exclude carrier status following appropriate genetic counselling.

View full test details for Fragile X (associated) Primary Ovarian Insufficiency (FXPOI); Premature Ovarian Failure 1 (POF1)

Introduction

Fragile X associated 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 of the FMR1 gene at Xq27.3, leading to increased transcription and a proposed toxic gain of function of FMR1 RNA.

Referral information

Testing is used for confirmation of a clinical diagnosis of FXTAS or for exclusion of the diagnosis in patients with relevant clinical indications. Within families with a history of FXTAS, testing is used to confirm a diagnosis or to establish or exclude carrier status following appropriate genetic counselling.

View full test details for Fragile X (associated) Tremor/Ataxia Syndrome (FXTAS)

Introduction

Fragile X syndrome is an X-linked disorder, characterized by moderate to severe mental retardation, macroorchidism, and distinct facial features, including long face, large ears, and prominent jaw, in males; with a milder phenotype in females.  In >99% of cases, the disorder is caused by the unstable expansion of a CGG repeat (to more than ~200 repeats)  in the FMR1 gene at Xq27.3 and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain.

Referral information

We accept referrals for confirmation of clinical diagnosis in patients meeting criteria issued by UKGTN referred with a fully completed UKGTN FMR1 form (female / male). Testing is also available for patients with a FMR1 associated disorder (FXTAS/FXPOI) and for families with a history of Fragile X syndrome.

View full test details for Fragile X Syndrome (FXS)

Introduction

In many patients with unexplained developmental delay, learning difficulties, multiple congenital abnormalities (MCA), behavioural disorders, dysmorphism or other developmental disorders, the conditions are caused by chromosome imbalance due to loss or gain of dosage sensitive genes or disruption of normal gene expression. The imbalance may be due to extra chromosomes (aneuploidy), unbalanced structural rearrangements or submicroscopic deletions or duplications.

Referral information

We accept blood (4ml in EDTA) or mouthwash samples from children and adults with a suspected chromosome imbalance. Follow up testing is also offered to family members of patients who have been diagnosed with chromosome imbalance to establish the inheritance of the imbalance and evaluate reproductive risks.

Microarray Comparative Genomic Hybridisation (aCGH) is used as the frontline test to detect chromosome imbalance. Microarray testing can detect chromosome deletions or gains at a higher resolution than routine chromosome analysis.

Microarray testing cannot detect balanced chromosome rearrangements or polyploidy and may not detect unbalanced rearrangements present in mosaic form.

Follow up testing may be performed by microarray, chromosome analysis or Fluorescence In Situ Hybridisation (FISH), as appropriate.

Neonates with referral reasons indicative of aneuploidy (trisomy for chromosomes 13, 18 or 21) or sex chromosome disorders will be processed by QF-PCR in the first instance followed by microarray as a reflex test if a normal result is obtained from QF-PCR. In cases where QF-PCR shows an aneuploidy result, chromosome analysis will be instigated to evaluate the genetic mechanism and thus the parental recurrent risk.

View full test details for Investigation of suspected chromosome imbalance in patients with learning difficulties multiple congenital abnormalities unexplained epilepsy or other developmental disorders

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.

Referral information

Prenatal referrals where a diaphragmatic hernia has been detected on ultrasound scan are tested for Pallister-Killian syndrome by microarray studies on an uncultured amniotic fluid sample. Pallister-Killian syndrome cannot be detected in blood samples and so this service is not offered. However, we do accept skin biopsy samples from patients with appropriate clinical features for a diagnosis of Pallister-Killian syndrome. It is recommended that a skin sample from more than one site is tested. Buccal swab samples may also be accepted for FISH studies to exclude i(12p), following prior arrangement with the laboratory.

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Introduction

Prader-Willi syndrome (PWS) is characterised by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is controlled by dietary restriction or behaviour modification). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment, although some will have an IQ within the normal range. A distinctive behavioural phenotype (with temper tantrums, stubbornness, manipulative behaviour, and obsessive compulsive characteristics) is common. Hypogonadism is present in both males and females, and manifests as genital hypoplasia, incomplete pubertal development, and in most, infertility. Short stature is common; characteristic facial features, strabismus, and scoliosis are often present, and non-insulin-dependent diabetes mellitus often occurs in obese individuals. Consensus diagnostic clinical criteria for PWS have been developed however confirmation of diagnosis requires genetic testing.

Prader-Willi syndrome (PWS) is usually sporadic in occurrence, and may arise from paternal deletion of 15q11-13 on chromosome 15 (~75-80% of cases); maternal uniparental disomy of chromosome 15 (~20-25% of cases) and imprinting defect (~ 1% of cases). (Ramsden et al, 2010, BMC Med. Genet., 11:70).

Referral information

We accept referrals of patients with appropriate signs and symptoms for a diagnosis of PWS.

View full test details for Prader-Willi Syndrome (PWS)