Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures

Almundher Al-Maawali, Brenda J. Barry, Anna Rajab, Malak El-Quessny, Ann Seman, Stephanie Newton Coury, A. James Barkovich, Edward Yang, Christopher A. Walsh, Ganeshwaran H. Mochida, Joan M. Stoler

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Exome sequencing identified homozygous loss-of-function variants in DIAPH1 (c.2769delT; p.F923fs and c.3145C>T; p.R1049X) in four affected individuals from two unrelated consanguineous families. The affected individuals in our report were diagnosed with postnatal microcephaly, early-onset epilepsy, severe vision impairment, and pulmonary symptoms including bronchiectasis and recurrent respiratory infections. A heterozygous DIAPH1 mutation was originally reported in one family with autosomal dominant deafness. Recently, however, a homozygous nonsense DIAPH1 mutation (c.2332C4T; p.Q778X) was reported in five siblings in a single family affected by microcephaly, blindness, early onset seizures, developmental delay, and bronchiectasis. The role of DIAPH1 was supported using parametric linkage analysis, RNA and protein studies in their patients' cell lines and further studies in human neural progenitors cells and a diap1 knockout mouse. In this report, the proband was initially brought to medical attention for profound metopic synostosis. Additional concerns arose when his head circumference did not increase after surgical release at 5 months of age and he was diagnosed with microcephaly and epilepsy at 6 months of age. Clinical exome analysis identified a homozygous DIAPH1 mutation. Another homozygous DIAPH1 mutation was identified in the research exome analysis of a second family with three siblings presenting with a similar phenotype. Importantly, no hearing impairment is reported in the homozygous affected individuals or in the heterozygous carrier parents in any of the families demonstrating the autosomal recessive microcephaly phenotype. These additional families provide further evidence of the likely causal relationship between DIAPH1 mutations and a neurodevelopmental disorder.

Original languageEnglish
Pages (from-to)435-440
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume170
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

Fingerprint

Microcephaly
Blindness
Seizures
Exome
Mutation
Bronchiectasis
Siblings
Epilepsy
Phenotype
Craniosynostoses
Nonsense Codon
Deafness
Hearing Loss
Knockout Mice
Respiratory Tract Infections
Stem Cells
Parents
Head
RNA
Cell Line

Keywords

  • Blindness
  • Deafness
  • DIAPH1
  • Intellectual disability
  • Microcephaly
  • Seizures

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures. / Al-Maawali, Almundher; Barry, Brenda J.; Rajab, Anna; El-Quessny, Malak; Seman, Ann; Coury, Stephanie Newton; Barkovich, A. James; Yang, Edward; Walsh, Christopher A.; Mochida, Ganeshwaran H.; Stoler, Joan M.

In: American Journal of Medical Genetics, Part A, Vol. 170, No. 2, 01.02.2016, p. 435-440.

Research output: Contribution to journalArticle

Al-Maawali, A, Barry, BJ, Rajab, A, El-Quessny, M, Seman, A, Coury, SN, Barkovich, AJ, Yang, E, Walsh, CA, Mochida, GH & Stoler, JM 2016, 'Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures', American Journal of Medical Genetics, Part A, vol. 170, no. 2, pp. 435-440. https://doi.org/10.1002/ajmg.a.37422
Al-Maawali, Almundher ; Barry, Brenda J. ; Rajab, Anna ; El-Quessny, Malak ; Seman, Ann ; Coury, Stephanie Newton ; Barkovich, A. James ; Yang, Edward ; Walsh, Christopher A. ; Mochida, Ganeshwaran H. ; Stoler, Joan M. / Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures. In: American Journal of Medical Genetics, Part A. 2016 ; Vol. 170, No. 2. pp. 435-440.
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