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Am J Med Genet A. 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.

Al-Maawali A1,2,3,4, Barry BJ1,2,3, Rajab A5, El-Quessny M1,2, Seman A1, Coury SN1, Barkovich AJ6, Yang E7,8, Walsh CA1,2,3,9,10,11, Mochida GH1,2,9,12, Stoler JM1,9.

Author information

Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts.
Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
National Genetics Center, Directorate General of Health Affairs, Ministry of Health, Muscat, Oman.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
Department of Radiology, Boston Children's Hospital, Boston, Massachusetts.
Department of Radiology, Harvard Medical School, Boston, Massachusetts.
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts.
Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.


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.


DIAPH1; blindness; deafness; intellectual disability; microcephaly; seizures

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