Familial campomelic dysplasia due to maternal germinal mosaicism

Higeta, Daisuke; Yamaguchi, Rie Shigetomi; Takagi, Takeshi; Nishimura, Gen; Sameshima, Kiyoko; Saito, Kayoko; Minegishi, Takashi

doi:10.1111/cga.12279

Cited by 2 publications

(1 citation statement)

References 5 publications

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“…Mutations detected in the propositus but absent from the parents are usually perceived as a de novo mutation in routine genetic testing using blood samples, but in fact, many apparently de novo mutations in the patient might be a consequence of somatic or germline mosaicism in unaffected parents (Campbell et al., 2014). Many apparently de novo mutations have been reported to be inherited from a parent with germline mosaicism and affect several Mendelian diseases, such as campomelic dysplasia (Higeta et al., 2018), fragile X syndrome (Jiraanont et al., 2016), and branchio‐oto syndrome (Miyagawa, Nishio, Hattori, Takumi, & Usami, 2015), and even accounted for 14.6% (6/41) of Duchenne muscular dystrophy cases (Bakker et al., 1989). The omission of germline mosaicism may lead to the recurrence of diseases and bring extra emotional and economic burdens to the affected family.…”

Section: Introductionmentioning

confidence: 99%

Identification of paternal germline mosaicism by MicroSeq and targeted next‐generation sequencing

Dai

Cheng

et al. 2020

Molec Gen & Gen Med

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Background Prezygotic de novo mutations may be inherited from parents with germline mosaicism and are often overlooked when the resulting phenotype affects only one child. We aimed to identify paternal germline mosaicism in an index family and provide a strategy to determine germline mosaicism.‘ Methods Whole‐exome sequencing was performed on an Alport syndrome‐affected child. Variants were validated using Sanger sequencing in the pedigree analysis. An apparent de novo mutation was tested by next‐generation sequencing (NGS) following chromosome microdissection of the mutant region (MicroSeq) to clarify its homologous chromosome source. Mosaic mutation in sperm samples was detected using targeted next‐generation sequencing (TNGS). Self‐prepared mosaic DNA samples of the 3% and 0.1% mutant fractions were used to evaluate the TNGS detection sensitivity. Results Two novel heterozygous variants, maternally inherited c.1322delT (p.Ile441Thrfs*17) and the de novo mutation c.2939T>A (p.Leu980Ter), in the COL4A3 gene were discovered in the propositus. MicroSeq identified c.2939T>A in the paternal chromosome, which was in trans with c.1322delT. The frequency of c.2937A was 2.65% in the father's sperm sample. We also showed that a 500X depth coverage may detect a mosaic mutation with an allele frequency as low as 2%–3% using TNGS. Conclusion MicroSeq is a valuable tool to identify the allele source of de novo mutations in a single patient. TNGS can be used to assess the mosaic ratios of known sites. We provided a systematic algorithm to detect germinal mosaicism in a single patient. This algorithm may have implications for genetic and reproductive counseling on germline mosaicism.

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Section: Introductionmentioning

confidence: 99%

Identification of paternal germline mosaicism by MicroSeq and targeted next‐generation sequencing

Dai

Cheng

et al. 2020

Molec Gen & Gen Med

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A Recurrent Rare SOX9 Variant (M469V) is Associated with Congenital Vertebral Malformations

Wang

et al. 2019

CGT

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Objective: The genetic variations contributed to a substantial proportion of congenital vertebral malformations (CVM). SOX9 gene, a member of the SOX gene family, has been implicated in CVM. To study the SOX9 mutation in CVM patients is of great significance to explain the pathogenesis of scoliosis (the clinical manifestation of CVM) and to explore the pathogenesis of SOX9-related skeletal deformities. Methods: A total of 50 singleton patients with CVM were included in this study. Exome Sequencing (ES) was performed on all the patients. The recurrent candidate variant of SOX9 gene was validated by Sanger sequencing. Luciferase assay was performed to investigate the functional changes of this variant. Results: A recurrent rare heterozygous missense variant in SOX9 gene (NM_000346.3: c.1405A>G, p.M469V) which had not been reported previously was identified in three CVM patients who had the clinical findings of congenital scoliosis without deformities in other systems. This variant was absent from our in-house database and it was predicted to be deleterious (CADD = 24.5). The luciferase assay demonstrated that transactivation capacity of the mutated SOX9 protein was significantly lower than that of the wild-type for the two luciferase reporters (p = 0.0202, p = 0.0082, respectively). Conclusion: This SOX9 mutation (p.M469V) may contribute to CVM without other systematic deformity, which provides important implications and better understanding of phenotypic variability in SOX9-related skeletal deformities.

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Familial campomelic dysplasia due to maternal germinal mosaicism

Cited by 2 publications

References 5 publications

Identification of paternal germline mosaicism by MicroSeq and targeted next‐generation sequencing

Identification of paternal germline mosaicism by MicroSeq and targeted next‐generation sequencing

A Recurrent Rare SOX9 Variant (M469V) is Associated with Congenital Vertebral Malformations

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