Introduction

Achondroplasia (ACH) is the most common form of disproportionate short stature in adults and children with an estamated prevalance of 1:27,000. Hypochondroplasia (HCH) with prevalence of approximately 1: 33, 000) closely resembles achondroplasia but with milder clinical presentation (less pronounced short stature and skeletal disproportion compared to achondroplasia).  Both conditions 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.

Referral information

Molecular confirmation of a clinical diagnosis or preceding a potential prenatal diagnosis where one or both parents have either condition. Prenatal diagnosis is also offered following skeletal indications of achondroplasia/hypochondroplasia on antenatal ultrasound scanning.

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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 1500 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.

Referral information

We accept referrals for mutation scanning to confirm or reduce the likelihood of a clinical diagnosis in children and adults with symptoms of cystic fibrosis and in whom no mutation or only one mutation has been identified. If a confirmed pathological mutation is identified we can offer carrier testing and prenatal diagnosis in at-risk family members.

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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.

Referral information

Confirmation of diagnosis where CF is clinically suspected. Testing of individuals in whom a diagnosis of a mild variant form of CF is suspected (for example, congenital bilateral absence of the vas deferens, CBAVD). Carrier screening of the partner and relatives of an individual who carries one or more common CF mutations. Carrier testing in pregnant couples with fetal echogenic bowel. Pre-natal diagnosis where specific parental mutations have been identified. For fetal echogenic bowel referrals, parental samples taken before PND allow a more rapid result. Ethnicity and whether the individual’s parents are consanguineous are required to calculate accurate risk figures. Where there is a family history we require either the mutation test results or a sample from the index case. We follow the UK Clinical Genetic Society guidelines on screening children and discourage carrier testing for minors in this condition.

View full test details for Cystic Fibrosis Common Mutation Screen

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 (~68%). Whole exon duplications are seen in ~10% of cases.

Referral information

We offer mutation screening for confirmation of a clinical diagnosis or suspicion of DMD or BMD. This may be followed up with carrier detection and prenatal diagnosis, as appropriate, with tests for a characterised mutation. Linkage analysis for carrier detection and prenatal diagnosis may be performed where there is a definite family history but a pathogenic mutation has not been identified.

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Introduction

Huntington Disease (HD) is an autosomal dominant disorder of the CNS, characterised by involuntary movements, impaired motor co-ordination and dementia. HD is caused by dynamic mutations of the (CAG)n tract in exon 1 of the Huntingtin gene (HTT) on chromosome 4p.16.3. Abnormally expanded CAG repeats in this region is thought to acquire a novel deleterious function which results in neuronal dysfunction and neurodegeneration. Age of onset is inversely correlated with number of CAG repeats.

Referral information

Diagnostic tests are ONLY accepted from Neurologists, Psychiatrists or Clinical Geneticists referring patients with definite motor signs of HD. A signed consent form is required (forms are available from www.mangen.org.uk). Pre-symptomatic testing is only offered in the context of the internationally agreed counselling protocol, and predictive test samples can ONLY from be accepted from Clinical Geneticists. Requests for prenatal diagnosis requests should also be referred through the Clinical Genetics Service.

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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.

Referral information

We accept referrals from Clinical Geneticists for tests in genes not offered as a service within the UK Genetic Testing Network. An application form for mutation confirmation can be downloaded from our website. This form must be completed for index cases only (see Useful Forms).

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Introduction

We offer a next generation sequencing screen of the whole coding sequence of PIK3CA and PTEN, as well as targeted screening of hotspot exons in PIK3R2, AKT1, AKT3, mTOR and CCND2. These genes are part of the phosphoinositide 3-kinase PI3K-Akt signalling pathway and both germline and post-zygotic mutations in these genes have been described associated with many segmental overgrowth syndromes.

Referral information

We offer mutation scanning in affected individuals and recommend testing a sample of DNA extracted from the overgrowth tissue to maximise the chances of mutation detection. The umbrella term of ‘segmental overgrowth syndromes’ encompasses disorders such as such as Megalencephaly-Capillary Malformation (MCM/MCAP) syndrome, Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus (MPPH) syndrome, Congenital Lipomatous Overgrowth Vascular Malformations, Epidermal Nevi and Skeletal abnormalities (CLOVES syndrome), Proteus syndrome and Cowden syndrome.

View full test details for Segmental Overgrowth Syndromes