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

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 identifieda 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.

Extension of the clinical and molecular phenotype of DIAPH1‐associated autosomal dominant hearing loss (DFNA1)

“…What could explain the assumed genotype-phenotype correlation, with the monoallelic DFNA1 mutations being confined to the C-terminus? Head circumference was normal in DFNA1 patients investigated by us, and hearing loss was not reported in patients with DIAPH1-related MCPH (33,34), supporting the concept of distinct mutation mechanisms underlying the allelic phenotypes. All known DFNA1 mutations fall into that range and hence could -in contrast to the MCPH-associated mutations -escape NMD and exert a gain-of-function effect.…”

Constitutive activation of DIA 1 ( DIAPH 1) via C‐terminal truncation causes human sensorineural hearing loss

“…In support of our hypothesis, the degenerative stereocilia phenotypes we observed in TG mice expressing the active DIA1 mutant, DIA1(R1204X), are similar to those observed in Cdc42‐KO mice. In addition to the absence of a hearing phenotype in Dia1‐KO mice in the present study, patients with loss of functional variants in DIA1 (p.Q778X, p.F923 fs, and p.R1049X) suffer from microcephalus, blindness, and seizure, but are not deaf (Al‐Maawali et al , ; Ercan‐Sencicek et al , ). Moreover, a transgenic Drosophila melanogaster strain with only one diaphanous gene and expression of a constitutive active form of diaphanous protein by removing both the N‐terminal GBD and the C‐terminal DAD showed impaired response to sound (Schoen et al , ).…”

“…Al-Maawali et al, 2016;Ercan-Sencicek et al, 2015). Moreover, a transgenic Drosophila melanogaster strain with only one diaphanous gene and expression of a constitutive active form of diaphanous protein by removing both the N-terminal GBD and the C-terminal DAD showed impaired response to sound(Schoen et al, 2010).…”

Lack of Diaph3 relaxes the spindle checkpoint causing the loss of neural progenitors

“…The severity of the Diaph3 phenotype (that is, embryonic lethality) might have precluded the establishment of a causal link between microcephaly and DIAPH3 loss-of-function mutations. Although mutations in DIAPH1 were associated with microcephaly in humans4849, neither Diaph1 or Diaph2 single ko , nor Diaph1 and Diaph2 dko have symptoms of primary microcephaly848. The involvement of Diaph3 in microcephaly suggests a functional redundancy and/or divergent roles of Diaphanous genes in humans and mice.…”