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Case Reports
.2016 Feb;170A(2):435-440.
doi: 10.1002/ajmg.a.37422. Epub 2015 Oct 13.

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

Affiliations
Case Reports

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

Almundher Al-Maawali et al. Am J Med Genet A.2016 Feb.

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.

Keywords: DIAPH1; blindness; deafness; intellectual disability; microcephaly; seizures.

© 2016 Wiley Periodicals, Inc.

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Conflict of interest statement

Conflict of interest: none.

Figures

FIG. 1
FIG. 1
Pedigrees of two consanguineous families with homozygous loss-of-function mutations inDIAPH1. Individuals with “MC” nomenclature represent DNA samples analyzed. (A) Family MC36500 is from the United Arab Emirates. (B) Family MC2500 is from Oman. MC2501 died of pneumonia, and MC-2502 died of seizures. IV:3 died of unknown causes but was not known to be similarly affected.
FIG. 2
FIG. 2
(A–C) brain MRI at 18 months. Sagittal T1 imaging demonstrates craniofacial disproportion and moderately depressed thickness of the posterior corpus callosum. There is preserved volume of the posterior fossa structures. (B) Axial T2 weighted imaging at the level of the internal capsules demonstrates pronounced T2 signal increase within the occipital poles suggestive of dysmyelination. The signal characteristics and myelination of the brain remain otherwise normal for age. (C) Axial T2 imaging at a lower level demonstrates grossly intact size of the optic nerves. The temporal lobes are small but in proportion to the remainder of the brain. (D) Axial T2 imaging of the brain at the level of the internal capsules, 9 months of age. The occipital pole signal abnormality is less conspicuous due to the early stage of myelination at this age. This exam also shows grossly intact cortical thickness and morphology.
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