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Case Reports
. 2015 Jun 25:16:41.
doi: 10.1186/s12881-015-0183-0.

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features

Muhammad Arshad Rafiq  1   2 , Claire S Leblond  3   4 , Muhammad Arif Nadeem Saqib  5 , Akshita K Vincent  6 , Amirthagowri Ambalavanan  7   8 , Falak Sher Khan  9 , Muhammad Ayaz  10 , Naseema Shaheen  11 , Dan Spiegelman  12   13 , Ghazanfar Ali  14 , Muhammad Amin-ud-Din  15 , Sandra Laurent  16   17 , Huda Mahmood  18 , Mehtab Christian  19 , Nadir Ali  20 , Alanna Fennell  21 , Zohair Nanjiani  22 , Gerald Egger  23   24 , Chantal Caron  25   26 , Ahmed Waqas  27 , Muhammad Ayub  28   29 , Saima Rasheed  30 , Baudouin Forgeot d'Arc  31   32   33 , Amelie Johnson  34   35 , Joyce So  36   37   38 , Muhammad Qasim Brohi  39 , Laurent Mottron  40   41   42 , Muhammad Ansar  43 , John B Vincent  44   45 , Lan Xiong  46   47   48
Affiliations
Case Reports

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features

Muhammad Arshad Rafiq et al. BMC Med Genet. .

Abstract

Background: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.

Methods: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.

Results: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.

Conclusion: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

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Figures

Fig. 1
Fig. 1
Pedigrees of the three Pakistani families. For family RQMR10, although the degree of relatedness between the parents of V-1, V-2, and V-3 could not be established, marriages within this rural community are strictly within the clan system, and thus they are almost certainly related. ATM02 is part of a much larger pedigree segregating ID, with 18 affected individuals, however only members of the portion indicated here was assessed in this study. This full pedigree is shown in Additional files 1, 2, 3 and 4
Fig. 2
Fig. 2
Photos of affected individuals from the three families
Fig. 3
Fig. 3
a Ideogram of chromosome 8, indicating location of HBD at 8q22. b Genomic organization of VPS13B/COH1, indicating location of the NM_017890.4:c.6879delT mutation (RQMR10 and ATM02) in exon 38, as well as the deleted region (exons 37–39) in ANMR51. c Electropherograms indicating the wild type homozygous (top), heterozygous (middle) and mutant homozygous (bottom) sequence across NM_017890.4:c.6879 (RQMR10 and ATM02). d Electropherogram from mRNA sequencing from an affected individual from ANMR51, indicating the (aberrant) splicing of exons 36 and 40
Fig. 4
Fig. 4
Homozygosity by descent of the Pakistani families and shared haplotype region for RQMR10 and ATM02. The homozygous-by-descent regions segregating with the phenotype within families RQMR10, ATM02 and ANMR51 are indicated with a dark blue, a green and a purple bar, respectively. The red bar indicates the region of shared haplotype for families RQMR10 and ATM02 and spans the entire VPS13B
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