SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis

Yang, Yongjia; Zheng, Yu; Li, Wangming; Li, Liping; Tu, Min; Zhao, Lingxia; Mei, Haibo; Zhu, Guoqiang; Zhu, Yimin

doi:10.1038/s41436-019-0552-8

Cited by 23 publications

(63 citation statements)

References 36 publications

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“…An enrichment of SMAD6 variants considered to be pathogenic has been reported in several pathologies distinct from CRS. [10][11][12][13][14][15][16][17] Using our variant categorization (based on AF and DS), we evaluated all SMAD6 variants that were previously reported as pathogenic. Systematic review identified 74 different SMAD6 variants, including 30 missense (Table S4, Fig.…”

Section: Re-evaluation Of Smad6 Variants Previously Reported As Pathomentioning

confidence: 99%

“…[7][8][9] Intriguingly, enrichment of rare SMAD6 variants has also been reported in association with several other distinct phenotypes, namely congenital heart disease, [10][11][12] bicuspid aortic valve (BAV) and ascending thoracic aortic aneurysm (TAA), [13][14][15] intellectual disability, 16 and radioulnar synostosis. 17 In a follow-up study, Timberlake et al increased the sample size of probands with midline CRS and no other genetic diagnosis to 379 (45 pedigrees included ≥1 additional affected family member). 18 They found damaging SMAD6 variants in 4/234 (1.7%) SS, 11/135 (8.1%) MS, and 2/10 (20%) combined metopic/sagittal synostosis probands.…”

Section: Introductionmentioning

confidence: 99%

“…Similar observations of nonpenetrance of SMAD6 variants were made for several of the other described disease associations. 13,14,17 To seek an explanation for the unpredictable penetrance, Timberlake et al 4,18 genotyped a single-nucleotide polymorphism (SNP), rs1884302, previously reported in a genome-wide association study (GWAS) of nonsyndromic SS to be the most significant associated SNP, which may differentially regulate the most proximal gene BMP2. 19,20 The risk-conferring C allele (prevalence in non-Finnish Europeans of 32.7%, gnomAD), 21 was found to be present in 15/21 individuals with CRS but only 1/20 unaffected relatives heterozygous for the SMAD6 variant but without CRS, suggesting a two-locus mechanism to account for variable manifestation of CRS.…”

Section: Introductionmentioning

confidence: 99%

“… 7 – 9 Intriguingly, enrichment of rare SMAD6 variants has also been reported in association with several other distinct phenotypes, namely congenital heart disease, 10 – 12 bicuspid aortic valve (BAV) and ascending thoracic aortic aneurysm (TAA), 13 – 15 intellectual disability, 16 and radioulnar synostosis. 17 …”

Section: Introductionmentioning

confidence: 99%

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SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Calpena

Cuellar

Bala

et al. 2020

Genetics in Medicine

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Purpose Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

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Section: Re-evaluation Of Smad6 Variants Previously Reported As Pathomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Calpena

Cuellar

Bala

et al. 2020

Genetics in Medicine

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“…We focused on 55 known causative genes for male DSD (Supplementary Table 6) (Eggers et al, 2016). We used the following filtering steps: (i) rare variants (MAF < 0.005, gnomAD_Eas); (ii) variants absent in in-house controls (201 ES data of males without DSD; parts are published before (Yang et al, 2019;Zhu et al, 2019); and (iii) considering damaging variants (loss-of-function and damaging missense variants) (Yang et al, 2019). Only one variant remained, namely, chr17:77753158, C to T (CBX2,NM_032647:exon3:c.117-3C > T) on A61 (Supplementary Figure 2A).…”

Section: None Of Seven Dsd-xyy Patients Harbor Pathogenic Variant On mentioning

confidence: 99%

Disorder of Sexual Development Males With XYY in Blood Have Exactly X/XY/XYY Mosaicism in Gonad Tissues

et al. 2021

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Y chromosome represents masculinization. The extra Y chromosome of XYY patients usually leads to over-masculinization phenotypes. The occurrence of several DSD cases with XYY in blood is controversial. Is XYY associated with disorder of sex development (DSD)? What is the mechanism behind DSD in males with XYY in blood? To this end, this study retrospectively analyzed blood-karyotype data of 4,437 DSD male children and karyotypes data of 6,259 newborn males as the control. Exome sequencing (ES) was performed to test whether the patients with DSD and with XYY in blood had other variants on known DSD-genes. Testicular biopsy was performed. Fluorescence in situ hybridization (FISH) was used to test whether a sex chromosome mosaicism was present in the oral epithelial cells or gonad tissue of patients with DSD and with XYY in blood. Among 4,437 DSD males who received cytogenetic evaluation, 14 patients with 47,XYY were identified. By contrast, five individuals among the 6,259 controls had 47,XYY. XYY in blood is more frequent among males with DSD than in other males (p = 0.004). The XYY karyotypes were confirmed again by GTG-banding in blood samples and by FISH performed on oral epithelial cells. ES on seven XYY DSD patients was successfully performed, but results did not identify any pathogenic variant on 55 known DSD genes. Gonad biopsy (n = 3) revealed testicular dysplasia and true hermaphroditism. FISH of gonad tissues (n = 3) showed that all of the samples had mosaic for X/XY/XYY. This study is the first to investigate the relationship between XYY in blood and DSD. The knowledge that XYY is in the blood and in oral cells have X/XY/XYY mosaicism in gonadal tissue is new for both researchers and clinicians who seek to understand the genetic basis of DSD males.

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