Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathiesReport as inadecuate

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, 1:18

First Online: 01 October 2012Received: 28 March 2012Accepted: 21 June 2012


BackgroundMeckel-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.

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

ResultsWe 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.

ConclusionsTMEM67 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.

KeywordsMeckel-Gruber syndrome Genotype-phenotype Founder mutation AbbreviationsBBSBardet-Biedl syndrome

JBTSJoubert syndrome

LCALeber congenital amaurousis

MKSMeckel-Gruber syndrome


SLSNSenior-Løken syndrome.

Electronic supplementary materialThe online version of this article doi:10.1186-2046-2530-1-18 contains supplementary material, which is available to authorized users.

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Author: Katarzyna Szymanska - Ian Berry - Clare V Logan - Simon RR Cousins - Helen Lindsay - Hussain Jafri - Yasmin Raashid - Sag


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