A novel homozygous mutation in TRAPPC9 gene causing autosomal recessive non-syndromic intellectual disability

Abstract

Background The etiology of intellectual disabilities is diverse and includes both genetic and environmental factors. The genetic causes of intellectual disabilities range from chromosomal aberrations to single gene disorders. The TRAPPC9 gene has been reported to cause autosomal recessive forms of intellectual disabilities in 56 patients from consanguineous and non-consanguineous families around the world. Methods We analyzed two siblings with intellectual disability, microcephaly and delayed motor and speech development from a consanguineous Sudanese family. Genomic DNA was screened for mutations using NGS panel (NextSeq500 Illumina) testing 173 microcephaly associated genes in the Molecular Genetics service in Robert Debre hospital in Paris, France. Results A novel homozygous mutation (NM_031466.7 (TRAPPC9):c.2288dup, p. (Val764Glyfs*7) in exon 14 of TRAPPC9 gene was found in the two patients. The mutation was predicted to cause nonsense mediated decay (NSMD) using SIFT prediction tool. The variant has not been found in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to the mutation. Conclusion This is the first study to report patients with TRAPPC9-related disorder from Sub-Saharan Africa.

Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice

“…In this study, we demonstrate by using MRI that the microcephaly of Trappc9 KO mice has a postnatal onset and is clearly established at weaning age. These findings are in line with TRAPPC9 patient data, which show microcephaly within the first year of life (Amin et al, 2022; Aslanger et al, 2022; Ben Ayed et al, 2021; Bolat et al, 2022; Hnoonual et al, 2019; Koifman et al, 2010; Penon-Portmann et al, 2023; Radenkovic et al, 2022) as well as data from other recently published Trappc9 KO mouse studies, which reported differences at postnatal days 7, 15 and 20, but not at birth (Hu et al, 2023; Ke et al, 2020). Monogenic disorders causing postnatal-onset microcephaly are less common than those causing primary microcephaly, which are mostly due to cell proliferation defects during embryogenesis.…”

“…One of the most consistent symptoms of patients with TRAPPC9 mutations is microcephaly, which has been detected in children as early as one year of age and includes reduced white matter (e.g. corpus callosum), cerebral and cerebellar atrophies (Amin et al, 2022; Aslanger et al, 2022; Ben Ayed et al, 2021; Bolat et al, 2022; Hnoonual et al, 2019; Koifman et al, 2010; Penon-Portmann et al, 2023; Radenkovic et al, 2022). To investigate microcephaly in homozygous Trappc9 mutant mice, we determined brain volumes via MRI as well as tissue weights at birth, weaning and adult stages.…”

“…Microcephaly in these patients was detectable by Magnetic Resonance Imaging (MRI) within the first year of life and included grey matter atrophies as well as white matter reductions (e.g. corpus callosum) (Amin et al, 2022; Aslanger et al, 2022; Ben Ayed et al, 2021; Bolat et al, 2022; Hnoonual et al, 2019; Koifman et al, 2010; Penon-Portmann et al, 2023; Radenkovic et al, 2022). Other disease symptoms occur more variably with obesity, dysmorphic facial features and hand-flapping movements being described in approximately half the patients (Aslanger et al, 2022; Bolat et al, 2022; Kramer et al, 2020).…”

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9

“…Human subject studies have suggested trappc9 to be a risk factor for obesity and NAFLD (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), but the relevant mechanism is not clear. In this study, we found that the deficiency of trappc9 resulted in the disruption of circulating glucose homeostasis, which was associated with hyperinsulinemia, hyperleptinemia, hyperprolactinemia, dyslipidemia, and reprogramming of glucose metabolism in the liver.…”

“…Loss-of-function mutations of the gene coding for the trafficking protein particle (TRAPP) complex subunit 9 (trappc9) cause an autosomal recessive syndrome with intellectual disability and malformations of various brain structures; over half of the cases exhibit obesity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Genome-wide analyses detect differential methylation of the trappc9 gene in children with severe obesity as well as in women with a high body-mass index (12)(13)(14) and link trappc9 to non-alcoholic fatty liver disease (NAFLD) (15), the most common liver disease frequently associated with obesity (16)(17)(18).…”