Whole Exome Sequencing reveals de novo mutations in POGZ and KMT2D genes of Iranian individuals with NDD

Introduction: Neurodevelopmental disorders are genetically and phenotypically heterogeneous disorders encompassingwide classification of intellectual disabilities (ID) and autism spectrum disorders. A combination of ASD with ID has beenobserved in 10%-40% of individuals thereby complicating diagnosis and treatment. Furthermore the biochemical andmolecular nature of ID and ASD pose an immense challenge to clinical geneticists in determining recurrence risk infamilies. The genetic etiology of autism spectrum disorders and intellectual disabilities remain poorly understood. Wholeexome sequencing offers high diagnostic yield in detection of heterogeneous disorders and identification of novel genes.Materials and Methods: Peripheral blood samples were collected from the patients and their family members afterobtaining written informed consent. Whole Exome Sequencing (WES) was initially performed on the proband to enrich allexons of protein-coding genes as well as adjacent nucleotide regions. Variants were analyzed using various bioinformaticsdatabases and software including PolyPhen, SIFT, Mutation Taster and CADD. Genomic DNA was analyzed by PCR andSanger sequencing using specific primers encompassing the exon and intronic boundaries of the identified variants inPOGZ and KMT2D genes.Results: Two Iranian families residing in Tehran, with no previous family history of genetic disorders, were investigated inthis study. Whole Exome Sequencing was conducted to identify the causative mutation in each family. DNA analysisassessed two novel mutations c.1918C> T and c.14531 delG in the POGZ and KMT2D genes respectively. The mutationsdid not segregate with the disease phenotype in the parents as expected, indicating the presence of new mutations in thefamilies.Discussion: This present study reports patients from two independent families with similar phenotypes of globalneurodevelopmental disorders primarily characterized by intellectual insufficiency, congenital malformations, delayedpsychomotor development and hypotonia having damaging mutations in the KMT2D and POGZ genes. Whole exomesequencing has played a significant role in detection of de novo mutations in heterogeneous disorders when chromosomalstudies are normal. De novo mutations substantially contribute to the occurrence of sporadic neurodevelopmental disorders.In this study we report for the first time two de novo mutations in KMT2D and POGZ genes in Iranian families with globaldevelopmental disorders. Our data incorporates to the available literature and enlightens a new era of genotype-phenotypecorrelation whereby first the gene is detected and subsequently linked to the disease phenotype. Molecular genetic testingwill accelerate and simplify genetic counselling and promote accurate and immediate prognostic information allowingpatients to benefit from precise diagnosis and risk assessment schemes for further conception.

کلیدواژه ها:

Whole Exome Sequencing (WES) ، De novo ، Genotype-Phenotype correlation ، Neurodevelopmental disorders