Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies

Cilia

Colin A Johnson⁵  Ruth Carlton²  Chris Bennett³  Mushtag Ahmed³  Bruce Castle¹  Saghira Malik-Sharif³  Yasmin Raashid⁴  Hussain Jafri⁴  Helen Lindsay²  Simon RR Cousins⁵  Clare V Logan⁵  Ian Berry²  Katarzyna Szymanska⁵ 

[1] Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK;Yorkshire Regional Genetics Service, St. James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK;Department of Clinical Genetics, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK;Department of Obstetrics & Gynaecology, King Edward Medical College, Lahore, Pakistan;Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK

关键词: Founder mutation;    Genotype-phenotype;    Meckel-Gruber syndrome;   

Others  :  793178
DOI  :  10.1186/2046-2530-1-18

 received in 2012-03-28, accepted in 2012-06-21,  发布年份 2012

【 摘 要 】

Background

Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal condition that is a ciliopathy. MKS has marked phenotypic variability and genetic heterogeneity, with mutations in nine genes identified as causative to date.

Methods

Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing.

Results

We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non-consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237) selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations.

Conclusions

TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546 + 1 G > A and c.870-2A > G) in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C > T p.R649X) and CC2D2A (c. 3540delA p.R1180SfsX6). Two missense mutations in TMEM67 (c. 755 T > C p.M252T, and c. 1392 C > T p.R441C) are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome.

【 授权许可】

   
2012 Szymanska et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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