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ObjectiveThis study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs).MethodsWe conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families.ResultsWES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: ABAT (c.1439 T > G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865_2865insT; p.Glu955Asnfs*5) [OMIM 218000], SHANK3 (c.1305-3_1,305-2delTT; p.Gln29-_Gly305del) [OMIM 606232], BCKDK (c.356_356insC; p.Gly119Alafs*24) [OMIM 614923], DDHD2 (c.2065G > T; p.Asp689Tyr) [OMIM 615033], ERCC2 (c.1255G > A; p.Glu419Lys) [OMIM 610756]. Additionally, 12 families had previously reported disease-causing variants associated with different types of NDDs: ATRX (c.109C > T; p.Arg37*) [OMIM 309580], GPR56 [ADGRG1] (c.1423C > T; p.Arg475*) [OMIM 606854], NAGLU (c.1694G > A; p.Arg565Gln) [OMIM 252920], DOLK (c.3G > A; p.Met1Ile) [OMIM 610768], GPT2 (c.815C > T; p.Ser272Leu) [OMIM 616281], DYNC1I2 (c.607 + 1G > A; p.?) [OMIM 618492], FBXL3 (c.885delT; p.Leu295Phefs25*) [OMIM 606220], LINGO1 (c.869G > A; p.Arg290His) [OMIM 618103], and ASPM (c.3978G > A; Trp1326*, c.9557C > G; p.Ser3186*, c.6994C > T; p.Arg2332*) [OMIM 608716]. All the identified variants showed segregation compatible with autosomal recessive inheritance.ConclusionIn the present study, we observed a high frequency of ASPM variants in the genetic analysis of 30 consanguineous families exhibiting features of NDDs, particularly those associated with autosomal recessive primary microcephaly. These findings contribute to studies on genotype–phenotype correlation, genetic counseling for families, and a deeper understanding of human brain function and development.

Background: Neurodevelopmental disorders are characterized by different combinations of intellectual disability (ID), communication and social skills deficits, and delays in achieving motor or language milestones. SLITRK2 is a postsynaptic cell-adhesion molecule that promotes neurite outgrowth and excitatory synapse development.Methods and Results: In the present study, we investigated a single patient segregating Neurodevelopmental disorder. SLITRK2 associated significant neuropsychological issues inherited in a rare X-linked fashion have recently been reported. Whole-exome sequencing and data analysis revealed a novel nonsense variant [c.789T>A; p.(Cys263*); NM_032539.5; NP_115928.1] in exon 5 of the SLITRK2 gene (MIM# 300561). Three-dimensional protein modeling revealed substantial changes in the mutated SLITRK2 protein, which might lead to nonsense-medicated decay.Conclusion: This study confirms the role of SLITRK2 in neuronal development and highlights the importance of including the SLITRK2 gene in the screening of individuals presenting neurodevelopmental disorders.