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An extremely severe phenotype attributed to WDR81 nonsense mutations

Nonsense Mutations Gerarda Cappuccio, MD,* Michele Pinelli, MD, PhD ,* Annalaura Torella, PhD, Giuseppina Vitiello, MD, Alessandra D’Amico, MD, Marianna Alagia, MD, Ennio Del Giudice, MD, Vincenzo Nigro, MD, TUDP, and Nicola Brunetti-Pierri, MD We read with great interest the article by Shaheen et al, who identified homozygous mutations in WDR81 gene (p.Gln1096* and p.Gly282Glu) in two independent families with congenital hydrocephalus and cerebellar malformation. First, we would like to add that another patient who died in the neonatal period with hydranencephaly and cerebellar hypoplasia with a homozygous p.Gly282Glu missense mutation in WDR81 has been previously reported Second, 2 other patients from independent families with cerebellar ataxia, intellectual disability, sensorineural hearing loss, and mild cerebellar atrophy were previously reported to carry another nonsense homozygous p.Arg1333* mutation in WDR81. These cases all had a more severe phenotype compared to patients with cerebellar ataxia, intellectual disability, and disequilibrium syndrome, in whom homozygous p.Pro856Leu mutations in WDR81 were first described. Third, we would like to report on a 17-year-old white female individual with an extremely severe phenotype harboring biallelic WDR81 nonsense mutations that we recently identified through whole-exome sequencing (WES) performed in a cohort of undiagnosed disease patients. The patient was born full term with microcephaly, respiratory distress, and neonatal seizures. She had bilateral ocular proptosis secondary to congenital glaucoma and facial dysmorphisms (Fig A). She did not acquire any developmental milestones. The brain magnetic resonance imaging showed a complex set of developmental anomalies, including severe microcephaly with an extremely thin and simplified gyral pattern of the frontal lobes together with an almost absent brain tissue peripherally to the dilated temporal horns, pontocerebellar hypoplasia, and corpus callosum agenesis with a single and dilated ventricular cavity (Fig B–D). Auditory brainstem responses and visual evoked potential were severely abnormal and the electroencephalogram showed an electrical activity of extremely low voltage. The clinical presentation was complicated by intestinal malrotation, frequent vomiting and chronic pancreatitis, and skeletal abnormalities, including ulnar and radial deviations, bilateral dislocation of the hip, and coccix agenesis. She also had an accessory spleen. A family-trio WES revealed that she was compound heterozygous for two nonsense mutations in the WDR81 gene: c.84G>A (p.Trp28*) in exon 2 that was also present in the father and c.1885C>T (p.Arg619*) in exon 9 that was present in the mother. In conclusion, we report on a patient with extremely severe neurological findings and a wide array of brain malformations attributed to nonsense mutations in WDR81 that appear to represent the severest end of the spectrum of the brain malformation recently described by Shaheen et al. In addition, the clinical picture in our patient was complicated by previously unreported extracerebral findings, including glaucoma, intestinal malrotation, chronic pancreatitis, and skeletal abnormalities, suggesting a pleiotropic function of WDR81.