De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism

Zawerton, Ash; Yao, Baojin; Yeager, J. Paige; Pippucci, Tommaso; Haseeb, Abdul; Smith, Joshua D.; Wischmann, Lisa; Kühl, Susanne J.; Dean, John; Pilz, Daniela T.; Holder, Susan; McNeill, Alisdair; Graziano, Claudio; Lefebvre, Véronique

doi:10.1016/j.ajhg.2019.01.014

Cited by 9 publications

(9 citation statements)

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“…gnomAD indeed contains multiple control individuals with variants in the HMG domain, and we showed in the case of SOX4 that these variants were retaining functions in vitro. 10 The identification of additional individuals with variants causing disease along with expansion of gnomAD should help future researchers establish algorithms to accurately make pathogenicity diagnoses for newly affected individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Immunoblots were carried out with FLAG M2-peroxidase-conjugated antibody (A8592, Sigma-Aldrich), P84 antibody (GTX70220-01, GeneTex), and b-actin antibody (sc-47778 [c4], Santa Cruz Biotechnology) as previously described. 10 The abilities of SOX6 variants to homodimerize and to bind DNA were tested upon transfection of COS-1 cells with ViaFect (3.5 mL) and empty or SOX6 expression plasmid (1,000 ng per 10 cm 2 dish). Whole-cell extracts were prepared after 40 h in 14 mM HEPES buffer (pH 7.9) containing 1.5 mM MgCl 2 , 6.0 mM KCl, 0.44 M NaCl, 0.08 mM EDTA, 2.3 mM DTT, 10% glycerol, and a protease inhibitor cocktail.…”

Section: Functional Assessment Of Sox6 Variants In Vitromentioning

confidence: 99%

“…Namely, the heterozygous loss of function of SOX5 (MIM: 604975) causes Lamb-Shaffer syndrome (LAMSHF [MIM: 616803]), which is associated with global developmental delay, intellectual disability, and mild dysmorphic features; 6,7 SOX11 (MIM: 600898) haploinsufficiency causes Coffin-Siris-like syndrome-9 (MIM: 615866), which is characterized by intellectual disability, microcephaly, and dysmorphic features; 8,9 and heterozygous de novo missense variants in SOX4 (MIM: 184430) cause Coffin-Siris-like syndrome-10 (MIM: 618506), which features intellectual disability and mild facial and digital skeletal abnormalities. 10 Human SOX6 (MIM: 607257) is located at 11p15 and is expressed in a variety of tissues. 11,12 Its mouse ortholog was shown to share essential redundant functions with its closest SOXD relative, Sox5, in the differentiation of chondrocytes 13,14 but to be uniquely expressed and exert other important functions in skeletal myoblast differentiation, 15 cardiomyocyte proliferation, 16 erythroid cell maturation, 17 and regulation of insulin secretion.…”

Section: Introductionmentioning

confidence: 99%

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

Tolchin

Yeager

Prasad

et al. 2020

The American Journal of Human Genetics

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Functional Assessment Of Sox6 Variants In Vitromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Tolchin

Yeager

Prasad

et al. 2020

The American Journal of Human Genetics

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“…The candidate genes associated with body size were SOX4, SALL3, and SIRT1 . SOX4 knockdown reduced brain and body size in Xenopus embryos [ 77 ]. SALL3 is associated with small body size in Chinese local chicken breeds [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

Origins, timing and introgression of domestic geese revealed by whole genome data

Wen

Wang

et al. 2023

J Animal Sci Biotechnol

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Background Geese are among the most important poultry species in the world. The current generally accepted hypothesis is that the European domestic geese originated from greylag geese (Anser anser), and Chinese domestic geese have two origins, most of which originated from swan geese (Anser cygnoides), and the Yili goose originated from greylag geese. To explain the origin and demographic history of geese, we selected 14 goose breeds from Europe and China and wild populations of swan and greylag geese, and whole genome sequencing data were obtained for 74 samples. Results Population structure analysis and phylogenetic trees showed that the wild ancestor of Chinese domestic geese, except for Yili, is the swan geese, and the wild ancestor of Chinese Yili and European domestic geese is greylag geese. Analysis of the demographic history suggests that the domestication of Chinese geese occurred ~ 3499 years ago and that of the European geese occurred ~ 7552 years ago. Furthermore, gene flow was observed between domestic geese and their wild ancestors. Analysis of introgression showed that Yili geese had been introgressed by Chinese domestic geese, and the body size of Yili geese may be influenced by introgression events of some growth-related genes, including IGF-1. Conclusions Our study provides evidence for the origin of geese at the genome-wide level and advances the understanding of the history of goose domestication and the traits affected by introgression events.

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“…For example, we are seeing a growing number of molecular causes of neurodevelopmental disorders (Arnett et al, 2021 ; Dinneen et al, 2021 ; Kiser et al, 2015 ) which often present with a complex phenotype with overlapping clinical features such as intellectual disability, behavioral changes, or nonspecific facial and digital skeletal abnormalities. This includes mutations in SOX genes that produce Coffin‐Siris‐like syndrome‐10 (OMIM: 618506; due to mutations in the SOX4 gene) (Zawerton et al, 2019 ), Lamb‐Shaffer syndrome (OMIM: 616803; due to mutations in the SOX5 gene) (Zawerton et al, 2020 ), or Coffin‐Siris‐like syndrome‐9 (OMIM: 615866; due to mutations in the SOX11 gene) (Hempel et al, 2016 ; Tsurusaki et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopmental disorder with dystonia due to SOX6 mutations

Schneider

Mueller

Biskup

et al. 2022

Molec Gen & Gen Med

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Background: Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities.To date, <25 cases have been reported in the literature. Methods and Findings: Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus. The clinical picture consisted of early onset mildly reduced intellectual function, facial asymmetry, and dystonic tremor of hands and neck, substantially improved by levodopa. Skeletal abnormalities included scoliosis and hypertrophy of the mandibular coronoid process. A heterozygous de novo loss-of-function variant in SOX6 (c.277 C>T. p.Arg93*) was molecularly confirmed which leads to truncation of the SOX6 protein in its N-terminus, upstream of any known functional domain.Conclusion: SOX6-associated neurodevelopmental delayis ultrarare with less than 25 cases described in the literature. We report a new case who presented with early-onset mildly reduced intellectual function, facial asymmetry, skeletal abnormalities and dystonic tremor of hands and neck, substantially improved by levodopa. Given the therapeutic implications, SOX6 mutations should be considered in patients with complex dystonia parkinsonism.

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De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism

Cited by 9 publications

References 0 publications

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

Origins, timing and introgression of domestic geese revealed by whole genome data

Neurodevelopmental disorder with dystonia due to SOX6 mutations

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