title: Genetic heterogeneity in Pakistani microcephaly families revisited.
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.
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: S M
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Genetic Engieneering and Biotechnology Institute, University of Baghdad, Baghdad, Iraq.
authors.forename: A R
authors.initials: AR
authors.lastname: Abdulkareem
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Hussain
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Sur
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: M R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Dalibor
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: A
authors.initials: A
authors.lastname: Moawia
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: S S
authors.initials: SS
authors.lastname: Waseem
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: M
authors.initials: M
authors.lastname: Asif
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: H
authors.initials: H
authors.lastname: Nagra
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: M
authors.initials: M
authors.lastname: Sher
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: M M A
authors.initials: MMA
authors.lastname: Khan
authors.affiliation: Plant Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: I
authors.initials: I
authors.lastname: Hassan
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: S Ur
authors.initials: SU
authors.lastname: Rehman
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: A A
authors.initials: AA
authors.lastname: Noegel
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
mesh_terms: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree; D000073359:Exome Sequencing
chemical_list: C467202:ASPM protein, human; C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins
keywords: ASPM; CDK5RAP2; MCPH; WDR62; founder mutation; splicing error