Abstract

Background: Neurodevelopmental disorders of genetic etiology are a highly diverse set of congenital recurrent complications triggered by irregularities in the basic tenets of brain development. Methods: We present whole exome sequencing analysis and expression characteristics of the probands from four unrelated Pakistani consanguineous families with facial dysmorphism, neurodevelopmental, ophthalmic, auditory, verbal, psychiatric, behavioral, dental, and skeletal manifestations otherwise unexplained by clinical spectrum. Results: Whole exome sequencing identifies a novel, bi-allelic, missense variant in the HGSNAT gene [NM_152419.3: c.1411G > A (p. Glu471Lys) exon 14] for proband family E-1 and a rare, bi-allelic, non-frameshift variant in the KDM6B gene [NM_001348716.2: c.786_791dupACCACC (p. Pro263_Pro264dup) exon 10] for proband family E-2, and a novel, mono-allelic, missense variant in the LMNA gene [NM_170707.4: c. 1328 A > G (p. Glu443Gly) exon 8] for proband family E-3 and an ultra-rare, mono-allelic, missense variant in the WFS1 gene [NM_006005.3: c.2131G > A (p. Asp711Asn) exon 8] for proband family E-4. Protein modelling shows conformation and size modifications in mutated residues causing damage to the conserved domains expressed as neurocognitive pathology. Conclusions: The current study broadens the distinctly cultural and genetically inbred pool of the Pakistani population for harmful mutations, contributing to the ever-expanding phenotypic palette. The greatest aspirations are molecular genetic profiling and personalized treatment for individuals with complex neurological symptoms to improve their life activities.