title: 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 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.
authors.affiliation: 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.
authors.forename: Almundher
authors.initials: A
authors.lastname: Al-Maawali
authors.affiliation: 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.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.affiliation: National Genetics Center, Directorate General of Health Affairs, Ministry of Health, Muscat, Oman.
authors.forename: Anna
authors.initials: A
authors.lastname: Rajab
authors.affiliation: 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.
authors.forename: Malak
authors.initials: M
authors.lastname: El-Quessny
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Ann
authors.initials: A
authors.lastname: Seman
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Stephanie Newton
authors.initials: SN
authors.lastname: Coury
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.affiliation: Department of Radiology, Boston Children's Hospital, Boston, Massachusetts.|Department of Radiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Edward
authors.initials: E
authors.lastname: Yang
authors.affiliation: 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 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.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: 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.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.|Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Stoler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000818:Animals; D001766:Blindness / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D000080865:Formins; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D012640:Seizures / Q000235:genetics* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins
keywords: DIAPH1; blindness; deafness; intellectual disability; microcephaly; seizures