Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

At least some cases of PSEK result from loss-of-function mutations in . Heterozygous missense substitutions in have been implicated in autosomal dominant monilethrix, a rare hair disorder. Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the gene. Together, these findings indicate that different types of mutations in can result in quite different skin and hair phenotypes.

Introduction: The study was designed to identify the genetic mutation in families with autosomal recessive primary microcephaly (MCPH). Methodology: The present study was cross-sectional and conducted at the Department of Biochemistry, Quaid-e-Azam University, Islamabad in 2017. The two families (A and B) with MCPH phenotype randomly selected from Hyderabad and Tando Adam districts respectively. Informed written consent was taken, physical parameters were measured and blood samples were collected from both families. DNA was extracted from whole blood and PCR was performed. The ASPM gene located on chromosome 1 is known to play a vital role in mitotic spindle fiber regulation during neurogenesis, and also is the most probable causative agent of microcephaly. Therefore targeted Sanger sequencing method for the ASPM gene was selected for variant identification in both families. Results: The Sanger sequencing result showed the novel missense variant (c.5841T/C; p. K1862E) in 18 exon of ASPM gene in Family A  and this variant predicted as damaging in mutation tester, and provean and also exhibited deleterious in Polyphen 2 and SIFT public database. Similarly in family B we found a previously reported protein pre termination variant (c.3978G/A; p.Trp1326*) (rs137852995) in exon 17 of ASPM gene. The later mutation was most predominant cause of microcephaly in KPK families. Conclusion: Therefore it is concluded that mutation in the ASPM gene is the most prominent genetic player of Microcephaly in Pakistani families. The current study aids in the genetic analysis of MCPH phenotype families in Pakistan alongwith the counseling of MCPH families.