A Two-Base Pair Deletion in IQ Repeats in ASPM Underlies Microcephaly in a Pakistani Family

Aims: Autosomal recessive primary microcephaly (MCPH) is a clinically rare and genetically highly heterogeneous developmental disorder. Biallelic variants in the abnormal spindle-like microcephaly-associated (ASPM) gene account for 40% to 68% of all MCPH cases. This study was designed to elucidate the genetic basis of MCPH in an extended family. To highlight recurrent mutations useful in implementing genetic testing programs, we further aimed to carry out a descriptive review of the reported ASPM mutations. Materials and Methods: A large inbred kindred with seven affected members was investigated, and detailed clinical and behavioral assessments were carried out. Single nucleotide polymorphism (SNP)-based homozygosity mapping and exome sequencing were performed. Results: Affected individuals had characteristic features, including small head, receding forehead, mild to moderate intellectual disability, developmental delay, short stature, apraxia, and behavioral anomalies. We mapped the disease gene locus and detected a rare frameshift deletion c.6854_6855del (p.(Leu2285GlnfsTer32)) in exon 18 of ASPM. A total of 215 mutations in ASPM have been reported in at least 453 families, nearly 50% of which are of Pakistani origin. These mutations can be classified as recurrent, founder or private in Pakistani and other populations. Conclusion: SNP-based homozygosity mapping and exome sequencing are essential in delineating the genetically distinct microcephaly types. The highlighted recurrent mutations in ASPM could be useful in implementing genetic testing programs for MCPH.