Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Am J Hum Genet. 2019 Sep 5;105(3):631-639. doi: 10.1016/j.ajhg.2019.07.002.

Björn Fischer-Zirnsak ¹, Lara Segebrecht ², Max Schubach ², Perrine Charles ³, Emily Alderman ⁴, Kathleen Brown ⁵, Maxime Cadieux-Dion ⁶, Tracy Cartwright ⁷, Yanmin Chen ⁸, Carrie Costin ⁹, Sarah Fehr ¹⁰, Keely M Fitzgerald ¹¹, Emily Fleming ¹², Kimberly Foss ¹³, Thoa Ha ¹⁴, Gabriele Hildebrand ¹, Denise Horn ¹, Shuxi Liu ⁸, Elysa J Marco ¹⁵, Marie McDonald ¹⁶, Kirsty McWalter ⁸, Simone Race ¹⁷, Eric T Rush ¹², Yue Si ⁸, Carol Saunders ¹⁸, Anne Slavotinek ¹⁴, Sylvia Stockler-Ipsiroglu ¹⁷, Aida Telegrafi ⁸, Isabelle Thiffault ¹⁸, Erin Torti ⁸, Anne Chun-Hui Tsai ¹⁹, Xin Wang ⁸, Muhammad Zafar ¹⁶, Boris Keren ³, Uwe Kornak ¹, Cornelius F Boerkoel ⁴, Ghayda Mirzaa ²⁰, Nadja Ehmke ²¹

Affiliations

1 Charité - Universitätsmedizin Berlin, Berlin 13353, Germany.
2 Charité - Universitätsmedizin Berlin, Berlin 13353, Germany; Berlin Institute of Health (BIH), Berlin 10117, Germany.
3 Department of Genetics, Assistance Publique - Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris 75013, France.
4 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
5 Department of Pediatrics, The Children's Hospital, University of Colorado School of Medicine, Aurora, CO 80045, USA.
6 Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals, Kansas City, MO 64108, USA.
7 Neuroscape Center, Departments of Neurology, Pediatrics, Physiology, Radiology, and Psychiatry, University of California, San Francisco, CA 94158, USA.
8 GeneDx, Gaithersburg, MD 20877, USA.
9 Akron Children's Hospital, Akron, OH 44302, USA.
10 Praxis für Humangenetik Tübingen, Tübingen 72076, Germany.
11 Division of Child Neurology, Department of Pediatrics, Children's Mercy Hospital & Clinics, Kansas City, MO 64108, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA.
12 Division of Clinical Genetics, Children's Mercy Hospital & Clinics, Kansas City, MO 64108, USA.
13 Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
14 Division of Genetics, Department Pediatrics, University of California, San Francisco, CA 94143-2711, USA.
15 Cortica Healthcare, San Rafael, CA 94903, USA.
16 Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
17 Division of Biochemical Genetics, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.
18 Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals, Kansas City, MO 64108, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA.
19 Department of Pediatrics, The Children's Hospital, University of Colorado School of Medicine, Aurora, CO 80045, USA; Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
20 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
21 Charité - Universitätsmedizin Berlin, Berlin 13353, Germany. Electronic address: [email protected].

PMID: 31353024 DOI: 10.1016/j.ajhg.2019.07.002

Abstract

Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.

Keywords

DLL1; Notch signaling; autism; brain malformation; developmental delay; intellectual disability; vertebral segmentation defects.

Name
Email *

	Sorry, but the email address you supplied was invalid.