当前位置： SCI文献检索 > AMERICAN JOURNAL OF HUMAN GENETICS期刊下所有文献 > De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Abstract：

:SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Tolchin D,Yeager JP,Prasad P,Dorrani N,Russi AS,Martinez-Agosto JA,Haseeb A,Angelozzi M,Santen GWE,Ruivenkamp C,Mercimek-Andrews S,Depienne C,Kuechler A,Mikat B,Ludecke HJ,Bilan F,Le Guyader G,Gilbert-Dussardier B,Ker

doi

10.1016/j.ajhg.2020.04.015

subject

Has Abstract

pub_date

2020-06-04 00:00:00

pages

830-845

issue

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(20)30124-5

journal_volume

106

pub_type

杂志文章

在线工具

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.