Neurodevelopmental disorders are a diverse group of illnesses characterized by impairments in personal, social, cognition, motor, or language skills as a result of abnormal brain development. One example of a neurodevelopmental disorder is intellectual disability. Genetic etiologies of ID were found to play a major role, and its prevalence is estimated to be three times more in countries known for consanguineous marriages. The burden of neurological genetic diseases in Oman is profound, especially with the increased incidence of autosomal recessive diseases. As a result, understanding the causes of intellectual disability will aid in providing specific counseling to families, thereby assisting in prevention. In recent years, Next Generation Sequencing has effectively accelerated ID research and provided novel therapeutic methods. Furthermore, Whole exome sequencing has been shown to be a powerful, robust, and scalable approach for discovering candidate genes, particularly in consanguineous populations. This study aimed to perform WES on patients affected with ID that are mainly born to a consanguineous family where the data collection was completed for 125 families with a total number of 224 affected patients. The variants identified after WES data analyses were prioritized, and Sanger sequencing was used for segregation analysis. Then, the diagnostic yield and clinical impact of variants identified in patients with suspected genetic diseases were established. Subsequently, functional characterization was carried out for selected candidate genes. Functional analyses were performed at the RNA level and protein level to confirm the pathogenic nature of the identified variant. Herein, Whole exome sequencing data analysis of 125 Omani families with neurodevelopmental disorders revealed a diagnostic rate of 31.2%. The consanguinity rate of the 125 families included in this study was found to be 88%. Following the ACMG guidelines of variant classification, pathogenic (P) or likely pathogenic (LP) variants were detected in 39/125 families (31.2%), with a total number of affected individuals was 56. Variants of uncertain significance were seen in 35/125 families (28%); these variants are rare, predicted to be damaging, segregated with the phenotype, and explain the disease manifestations. Candidate genes with a possible association with the phenotype seen in our families were detected in 30/125 (24%) with a total number of affected individuals of 64. For all variants in candidate genes, family pedigrees were included up to 3 generations. The total number of candidate genes identified was 28. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CDC42BPB, CNP, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28 Furthermore, 3 candidate genes with possible causative variants were selected for functional characterization. In a family (10MS13800) with four affected individuals, a homozygous 28-nucleotide frameshift deletion introducing a premature stop codon in the PTRHD1 exon 1 was discovered. It was additionally confirmed that the aberrant transcript escaped from the nonsense-mediated messenger RNA (mRNA) decay pathway. Real time PCR showed that mRNA expression of the mutant PTRHD1 is higher compared to the wild type. Using the patient's primary cells, western blotting and isoelectric focusing revealed a truncated but stable mutant PTRHD1 protein. The study provided further evidence that PTRHD1 mutations are associated with autosomal-recessive childhood onset intellectual disability as well as spasticity and parkinsonism. Another family (16MS3000) with four affected newborns was reported. They all presented with congenital microcephaly which led to death within the first few months of life. Initial research exome sequence analysis of the proband identified a highly damaging NME1 homozygous variant as a possible novel cause of primary microcephaly phenotype in humans. Results of In-vitro studies including western blot and immunoprecipitation unproven NME1 variants as the cause of the phenotype. Regular reanalysis of the exome for this family (16MS3000) uncovered the actual cause, which is the biallelic ASNS non coding variant. Reverse Transcription (RT-PCR) using the patient's primary cell line confirmed that the aberrant transcript was stable and escape NMD-pathway. Conversely, mutant cDNA sequencing showed that there is an abnormal insertion of 4 bp (GTAG) from intron 6 into exon 7 in comparison to wild-type cDNA. Western blotting showed that ASNS protein in the affected patient's lysate was not detected which indicated aberrant degradation of the protein. Furthermore, the biochemical analysis showed that Cerebrospinal fluid (CSF) asparagine level was not detectable. These results suggested that the phenotype in the family is due to the ASNS variant.