Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies.
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.
Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St, James's University Hospital, Leeds, UK. c.johnson@leeds.ac.uk.
Katarzyna
K
Szymanska
Ian
I
Berry
Clare V
CV
Logan
Simon Rr
SR
Cousins
Helen
H
Lindsay
Hussain
H
Jafri
Yasmin
Y
Raashid
Saghira
S
Malik-Sharif
Bruce
B
Castle
Mushtag
M
Ahmed
Chris
C
Bennett
Ruth
R
Carlton
Colin A
CA
Johnson