Identifying gene variants implicated in rare recessive disorders with Sensorineural hearing loss and Amelogenesis imperfecta

  • Nada Alsheqaih

Student thesis: Phd


Heimler syndrome (HS; MIM# 234580) is a rare recessive disorder characterised by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and, in some patients, retinal pigmentation. The genetic cause of HS is unknown. Here I present a study of eight HS families. Whole exome sequencing, SNP arrays and Sanger sequencing led to biallelic mutations being discovered in PEX1 or PEX6 in six of the families. Loss-of-function mutations in both PEX1 and PEX6 are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. However here I show that hypomorphic mutations or the combination of a loss of function and a hypomorphic mutation lead to HS. Additional work, including electron microscopy and western blotting, was performed in fibroblast cells from available cases to characterise the functional consequences of the mutations. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, my findings with collaborators define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6. The project aimed to define the genotypic and phenotypic spectrum associated with mutations in PEX1 and PEX6 genes. An additional family with HS was ascertained and I identified a novel homozygous mutation in PEX1. In one HS phenotype family, no mutation in PEX1 or PEX6 genes was identified. However, a blended phenotype has emerged as the likely explanation for the phenotype. This family has a milder clinical presentation to the PEX1 and PEX6 associated cases. In this family, two independent genes are responsible for the SNHL and the amelogenesis imperfecta phenotypes. The genetic cause behind SNHL was identified due to a biallelic deletion of the STRC/CATSPER2 genes that are known to be responsible for SNHL and male infertility. The genetic cause behind amelogenesis imperfecta is still unknown. Following the success in HS gene identification, I explored the opportunity to identify the causative genes in rare syndromes with other forms of amelogenesis imperfecta and SNHL. In a consanguineous Moroccan family with SNHL and amelogenesis imperfecta using autozygosity mapping and whole exome sequencing I identified a novel homozygous mutation in FAM20C. Mutations in FAM20C result in Raine syndrome (RS), a rare recessive disorder characterised by SNHL, amelogenesis imperfecta, osteosclerotic bone dysplasia, severe craniofacial anomalies often resulting in infant death. Only a few cases have been reported with individuals who survived childhood due to hypomorphic mutations.
Date of Award31 Dec 2018
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorGraeme Black (Supervisor) & William Newman (Supervisor)


  • Sensorineural hearing loss (SNHL)
  • Heimler syndrome
  • Raine syndrome
  • Heimler like syndrome
  • Amelogenesis imperfecta (AI)

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