Skip to main content

Exome sequencing and functional studies in human neurodevelopmental disorders: novel genes and phenotypes

Wednesday, September 12, 2018 — Poster Session I

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • J Stephen
  • C Rivas
  • S Nampoothiri
  • A Elkahloun
  • JD Burke
  • UDN Network
  • S Maddirevula
  • AB Kulkarni
  • A Shukla
  • HD Morris
  • SJ Patil
  • A Rauch
  • P Joset
  • JA Martinez-Agosto
  • LJ Garrett
  • FS Alkuraya
  • T Yokoyama
  • WA Gahl
  • N Balanda
  • MCV Malicdan


Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogenous conditions caused due to defects in genes involved in growth and development of nervous system. This study describes similarly affected individuals from five families having neurodevelopmental delay, facial dysmorphism (FD) and congenital heart defects (CHD); and a single family with two affected children having severe microcephaly and cerebral atrophy. In five families, whole exome sequencing (WES) revealed bi-allelic mutations in TMEM94 gene, that is ubiquitously expressed, highly conserved and has over 90% protein similarity across mammals. Gene expression analysis in cells from the affected individuals revealed reduced expression of TMEM94 and altered global gene expression network. Tmem94-/- mice generated were embryonic lethal and manifested hemorrhage, facial dysmorphism and cardiac abnormalities. Histopathological staining at E15.5 and E18.5 stages showed abnormal neuronal migration, hemorrhage and atrioventricular septal defects as the cause of embryonic lethality. In the family with microcephaly and seizures, WES identified bi-allelic mutations in VARS that encodes cytoplasmic valyl tRNA synthetase. cDNA analysis on patient cells revealed that the splice site mutant allele results to a null allele. 3D modelling of VARS predicts that missense mutation lies in the highly-conserved region and could alter side chain packing and destabilize the interface between the catalytic and tRNA binding domains. Expression and aminoacylation studies showed remarkably reduced level of VARS in mRNA and protein level and markedly reduced enzyme activity suggesting the mutations to be loss of function. To conclude, our study reports a novel syndrome of NDD with facial dysmorphism and CHD, first Tmem94-/- animal model and adds novel genes associated with NDD to the medical literature.

Category: Genetics and Genomics