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Am J Hum Genet. 2019 Apr 4;104(4):701-708. doi: 10.1016/j.ajhg.2019.02.002. Epub 2019 Mar 14.

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder.

Author information

1
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
2
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA.
3
Department of Neurology, University of Alabama Birmingham, Birmingham, AL 35294, USA.
4
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
5
Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris 75013, France; Centres de Référence Maladies Rares, Déficiences Intellectuelles de Causes Rares, Paris 75013, France; Groupes de Recherche Clinique Paris Sorbonne Déficience Intellectuelle et Autisme, Paris 75013, France.
6
Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris 75013, France; Faculté de Médecine, Institut du Cerveau et de la Moelle épinière, Sorbonne Université, Paris 75013, France.
7
Faculté de Médecine, Institut du Cerveau et de la Moelle épinière, Sorbonne Université, Paris 75013, France; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany.
8
Connecticut Children's Medical Center, Farmington, CT 06032, USA.
9
Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland; Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program, University of Zurich, Zurich 8032, Switzerland.
10
Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland.
11
GeneDx, Gaithersburg, MD 20877, USA.
12
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: gcooper@hudsonalpha.org.

Abstract

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10-6). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.

KEYWORDS:

BRSK2; Mendelian disease; clinical sequencing; de novo; developmental delay; exome; genome; intellectual disability

PMID:
30879638
PMCID:
PMC6451696
[Available on 2019-10-04]
DOI:
10.1016/j.ajhg.2019.02.002

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