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Compound heterozygous ASPM mutations in Pakistani MCPH families
Author(s) -
Muhammad Farooq,
Mahmood Baig Shahid,
Hansen Lars,
Sajid Hussain Muhammad,
Anjum Inayat Iram,
Aslam Muhammad,
Anver Qureshi Javed,
Toilat Muhammad,
Kirst Elisabeth,
Wajid Muhammad,
Nürnberg Peter,
Eiberg Hans,
Tommerup Niels,
Kjaer Klaus W.
Publication year - 2009
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.32749
Subject(s) - genetics , loss of heterozygosity , compound heterozygosity , biology , haplotype , allele , gene
Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (≤4 SD) and mental retardation without any other neurological manifestation. Of the four identified MCPH genes, homozygous truncating mutations in ASPM (MCPH5) account for >50% of all reported families. In spite of the high frequency of MCPH in Pakistan only one case of compound heterozygosity for mutations in ASPM has been reported yet. In this large MCPH study we ascertained 37 families including 319 persons (140 patients). Haplotype analysis of eight STS markers suggested linkage by homozygosity in 20 families, and re‐analysis of single sib ships in the remaining families demonstrated possible compound heterozygosity in two families. Direct sequencing indeed confirmed compound heterozygosity in two and homozygous mutations in 20 families, respectively, showing that up to 10% of families with MCPH caused by ASPM are compound heterozygous. In total we identified 16 different nonsense or frameshift mutations of which 12 were novel thereby increasing the number of mutations in ASPM significantly from 35 to 47. We found no correlation between the severity of the condition and the site of truncation. We suggest that the high frequency of compound heterozygosity observed in this study is taken into consideration as part of future genetic testing and counseling in Pakistani MCPH families. © 2009 Wiley‐Liss, Inc.