Whole Exome Sequencing Reveals Two Novel Homozygous Variants in the TRAPPC9 and PLOD3 Genes Leading to Intellectual Disability and Bone Fragility with Contractures

Abstract

Salt and Pepper’ syndrome is an autosomal recessive condition characterized by severe intellectual disability (ID), epilepsy, scoliosis, choreoathetosis, dysmorphic facial features, and altered dermal pigmentation. IDs are heterogeneous group of disorders prevalent in highly consanguineous populations and genetically variable condition of cognitive impairment linked with behavioral, syndromic, or dysmorphic features. Trafficking protein particle complex subunit 9 ( TRAPPC9) (MIM 611966) is an important gene, and mutations in this gene have been reported to be involved in ID conditions. Lysyl hydroxylase 3 (encoded by ( PLOD3)) is a multifunctional enzyme responsible for catalyzing hydroxylation of lysyl residues and O-glycosylation of hydroxylysyl residues, an important step during posttranslational modifications for collagen biosynthesis. In this study, whole exome sequencing was done for a family member having ID, microcephaly, included joint contractures, low bone mineral density, and dysmorphic feature. We identified a novel missense variant (NM_001160372.3) c.3211G>A, p.G1071S in the exon 22 of TRAPPC9 causing ID and other missense variant c.346G>A, p.V116M (NM_001084.4) in the exon 4 of the PLOD3 gene causing bone fragility with contractures in the affected member of the family. The obtained results were further validated by using Sanger sequencing analysis. The identified variant has not been reported in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to these identified mutations. Our results for the first time suggest that identified novel TRAPPC9 and PLOD3 gene mutations are the main cause of the disease leading to the ID-associated conditions along with cognitive deficits along with microcephaly. This is the first study to report patients with TRAPPC9- and PLOD3-related disorder from Saudi Arabia. This study will add to the literature of the disease and will enable the creation of a database that will provide a strong base to understanding the critical genomic regions to control ID and related disorders in Saudi patients.