Madelyn A. Gillentine
Tianyun Wang
Kendra Hoekzema
Jill Rosenfeld
Pengfei Liu
Hui Guo
Chang N. Kim
Bert B A De Vries
Lisenka E L M Vissers
Magnus Nordenskjold
Malin Kvarnung
Anna Lindstrand
Ann Nordgren
Jozef Gecz
Maria Iascone
Anna Cereda
Agnese Scatigno
Silvia Maitz
Ginevra Zanni
Enrico Bertini
Christiane Zweier
Sarah Schuhmann
Antje Wiesener
Micah Pepper
Heena Panjwani
Erin Torti
Farida Abid
Irina Anselm
Siddharth Srivastava
Paldeep Atwal
Carlos A. Bacino
Gifty Bhat
Katherine Cobian
Lynne M. Bird
Jennifer Friedman
Meredith S. Wright
Bert Callewaert
Florence Petit
Sophie Mathieu
Alexandra Afenjar
Celenie K. Christensen
Kerry M. White
Orly Elpeleg
Itai Berger
Edward J. Espineli
Christina Fagerberg
Charlotte Brasch-Andersen
Lars Kjærsgaard Hansen
Timothy Feyma
Susan Starling Hughes, Children's Mercy HospitalFollow
Isabelle Thiffault, Children's Mercy HospitalFollow
Bonnie Sullivan, Children's Mercy HospitalFollow
Shuang Yan, Children's Mercy Hospital
Kory Keller
Boris Keren
Cyril Mignot
Frank Kooy
Marije Meuwissen
Alice Basinger
Mary Kukolich
Meredith Philips
Lucia Ortega
Margaret Drummond-Borg
Mathilde Lauridsen
Kristina Sorensen
Anna Lehman
Elena Lopez-Rangel
Paul Levy
Davor Lessel
Timothy Lotze
Suneeta Madan-Khetarpal
Jessica Sebastian
Jodie Vento
Divya Vats
L Manace Benman
Shane Mckee
Ghayda M. Mirzaa
Candace Muss
John Pappas
Hilde Peeters
Corrado Romano
Maurizio Elia
Ornella Galesi
Marleen E H Simon
Koen L I van Gassen
Kara Simpson
Robert Stratton
Sabeen Syed
Julien Thevenon
Irene Valenzuela Palafoll
Antonio Vitobello
Marie Bournez
Laurence Faivre
Kun Xia
SPARK Consortium
Rachel K. Earl
Tomasz Nowakowski
Raphael A. Bernier
Evan E. Eichler

Document Type


Publication Date



DOI: 10.1186/s13073-021-00870-6; PMCID: PMC8056596


BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Journal Title

Genome Med





First Page


Last Page



Cortex development; Gene families; Neurodevelopmental disorders; hnRNPs


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