Compound heterozygous ASPM mutations in Pakistani MCPH families

TY - JOUR

T1 - Compound heterozygous ASPM mutations in Pakistani MCPH families

AU - Muhammad, Farooq

AU - Mahmood Baig, Shahid

AU - Hansen, Lars

AU - Sajid Hussain, Muhammad

AU - Anjum Inayat, Iram

AU - Aslam, Muhammad

AU - Anver Qureshi, Javed

AU - Toilat, Muhammad

AU - Kirst, Elisabeth

AU - Wajid, Muhammad

AU - Nürnberg, Peter

AU - Eiberg, Hans

AU - Tommerup, Niels

AU - Kjaer, Klaus W

N1 - Keywords: Haplotypes; Heterozygote; Humans; Microcephaly; Mutation; Nerve Tissue Proteins; Pedigree

PY - 2009

Y1 - 2009

N2 - Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (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.

AB - Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (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.

U2 - 10.1002/ajmg.a.32749

DO - 10.1002/ajmg.a.32749

M3 - Journal article

C2 - 19353628

SN - 1552-4825

VL - 149A

SP - 926

EP - 930

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

IS - 5

ER -