Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females

Am J Hum Genet. 2016 Sep 1;99(3):728-734. doi: 10.1016/j.ajhg.2016.06.028.

Jennifer M Bain ¹, Megan T Cho ², Aida Telegrafi ², Ashley Wilson ³, Susan Brooks ⁴, Christina Botti ⁴, Gordon Gowans ⁵, Leigh Anne Autullo ⁵, Vidya Krishnamurthy ⁶, Marcia C Willing ⁷, Tomi L Toler ⁷, Bruria Ben-Zev ⁸, Orly Elpeleg ⁹, Yufeng Shen ¹⁰, Kyle Retterer ², Kristin G Monaghan ², Wendy K Chung ¹¹

Affiliations

1 Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
2 GeneDx, Gaithersburg, MD 20877, USA.
3 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
4 Department of Pediatrics, Rutgers Robert Wood Johnson Medical Group, New Brunswick, NJ 08901, USA.
5 Weisskopf Child Evaluation Center, University of Louisville, Louisville, KY 40202, USA.
6 Pediatrics & Genetics, Alpharetta, GA 30005, USA.
7 Division of Genetics & Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
8 Pediatric Neurology, Edmond and Lily Safra Children's Hospital at Sheba, Derech Sheba 2, Tel Hashomer, Ramat Gan, Israel.
9 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
10 Departments of Biomedical Informatics and Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
11 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: wkc15@columbia.edu.

PMID: 27545675 DOI: 10.1016/j.ajhg.2016.06.028

Abstract

Via whole-exome Sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.

Keywords

HNRNPH2; X chromosome; alternative splicing; autism; developmental delay; microcephaly; neurodevelopment; pre-mRNA.

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