Format

Send to

Choose Destination
Clin Genet. 2017 Jul;92(1):62-68. doi: 10.1111/cge.12955. Epub 2017 Feb 22.

Genetic heterogeneity in Pakistani microcephaly families revisited.

Author information

1
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
2
Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
3
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
4
Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
5
Genetic Engieneering and Biotechnology Institute, University of Baghdad, Baghdad, Iraq.
6
Plant Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
7
Institute of Human Genetics, University of Cologne, Cologne, Germany.
8
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

Abstract

Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.

KEYWORDS:

ASPM; CDK5RAP2; MCPH; WDR62; founder mutation; splicing error

PMID:
28004384
DOI:
10.1111/cge.12955
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center