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Am J Med Genet A. 2017 Nov;173(11):3003-3012. doi: 10.1002/ajmg.a.38492. Epub 2017 Sep 25.

De novo mutations in HNRNPU result in a neurodevelopmental syndrome.

Author information

1
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
2
Department of Clinical Genetics, University Hospitals of Leicester, Leicester, UK.
3
Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust/City Hospital, Belfast, Northern Ireland, UK.
4
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK.
5
Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
6
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
7
Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
8
Broad Center for Mendelian Genomics, Cambridge, Massachusetts.
9
DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Abstract

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

KEYWORDS:

HNRNPU; aggressive outbursts; behavior; intellectual disability; seizures; trio exome sequencing

PMID:
28944577
PMCID:
PMC6555908
DOI:
10.1002/ajmg.a.38492
[Indexed for MEDLINE]
Free PMC Article

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