TY - JOUR
T1 - Gene constraint and genotype–phenotype correlations in neurodevelopmental disorders
AU - Betancur, Catalina
AU - Buxbaum, Joseph D.
N1 - Funding Information:
This work was supported by the Beatrice and Samuel A. Seaver Foundation (to JDB) and by the National Institute of Mental Health ( MH111661 , to CB and JDB, and, MH097849 to JDB).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/12
Y1 - 2020/12
N2 - With the advent and widespread adoption of high-throughput DNA sequencing, genetic discoveries in neurodevelopmental disorders (NDDs) are advancing very rapidly. The identification of novel NDD genes and of rare, highly penetrant pathogenic variants is leading to improved understanding of genotype–phenotype correlations. Here we emphasize the importance of large-scale, reference databases such as gnomAD to determine gene and variant level constraints and facilitate gene discovery, variant interpretation, and genotype–phenotype correlations. While the majority of dominant NDD genes are highly intolerant to variation, some apparent exceptions in reference databases are related to the presence of variants in transcripts that are not brain expressed and/or genes that show acquired somatic mosaicism in blood. Multiple NDD genes are being identified where varying phenotypes depend on the mode of inheritance (e.g., dominant or recessive), the nature (e.g., missense or truncating), or location of the mutation. Ongoing genome-wide analyses and targeted functional studies provide enhancements to the annotation of genes, gene products and variants, which will continue to facilitate gene and variant discovery and variant interpretation.
AB - With the advent and widespread adoption of high-throughput DNA sequencing, genetic discoveries in neurodevelopmental disorders (NDDs) are advancing very rapidly. The identification of novel NDD genes and of rare, highly penetrant pathogenic variants is leading to improved understanding of genotype–phenotype correlations. Here we emphasize the importance of large-scale, reference databases such as gnomAD to determine gene and variant level constraints and facilitate gene discovery, variant interpretation, and genotype–phenotype correlations. While the majority of dominant NDD genes are highly intolerant to variation, some apparent exceptions in reference databases are related to the presence of variants in transcripts that are not brain expressed and/or genes that show acquired somatic mosaicism in blood. Multiple NDD genes are being identified where varying phenotypes depend on the mode of inheritance (e.g., dominant or recessive), the nature (e.g., missense or truncating), or location of the mutation. Ongoing genome-wide analyses and targeted functional studies provide enhancements to the annotation of genes, gene products and variants, which will continue to facilitate gene and variant discovery and variant interpretation.
UR - http://www.scopus.com/inward/record.url?scp=85086863763&partnerID=8YFLogxK
U2 - 10.1016/j.gde.2020.05.036
DO - 10.1016/j.gde.2020.05.036
M3 - Review article
C2 - 32599522
AN - SCOPUS:85086863763
SN - 0959-437X
VL - 65
SP - 69
EP - 75
JO - Current Opinion in Genetics and Development
JF - Current Opinion in Genetics and Development
ER -