Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6MFSD2AANKLE2 and CIT (Khan et al.2014; Yamamoto et al.2014; Alakbarzade et al.2015; Morris-Rosendahl and Kaindl 2015; Basit et al.2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C > T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain.
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We extend special thanks to all family members for their volunteer participation in this study. The current study is partially supported by startup research grant from Higher Education Commission of Pakistan (M-IPFP/HRD/HEC/2011/346) for molecular screening of neurological disorders. MAK appreciates the valuable contribution of his beloved nephew, Abdul Ahad Khan Gandapur in recruiting the family.
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