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MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene.

ABSTRACT: MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype-phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435?G?>?T; p.Ala1479Ser).

SUBMITTER: Onuma S

PROVIDER: S-EPMC7057985 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene.

Onuma Shinsuke S Wada Tamaki T Araki Ryosuke R Wada Kazuko K Tanase-Nakao Kanako K Narumi Satoshi S Fukui Miho M Shoji Yasuko Y Etani Yuri Y Ida Shinobu S Kawai Masanobu M

Human genome variation 20200305

MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype-phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435 G > T; p.Ala1479Ser). ...[more]

PMID: 32194975

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Acquired uniparental disomy of chromosome 7 in a patient with MIRAGE syndrome that veiled a pathogenic SAMD9 variant.

Project description:Gain-of-function variants in SAMD9, which resides on chromosome 7, cause MIRAGE syndrome that is associated with congenital adrenal insufficiency and gonadal dysgenesis. We previously reported a Japanese patient with MIRAGE syndrome carrying a de novo heterozygous SAMD9 variant (p.Ala1479Ser). In this study, we confirmed the pathogenicity of Ala1479Ser-SAMD9 in vitro. Genetic study results revealed an atypically low variant allele frequency (26%) and we suspected of genomic rearrangement(s) involving chromosome 7. Single nucleotide polymorphism (SNP) array and short tandem repeat analysis showed presence of mosaic maternal isodisomic uniparental disomy 7 (UPD7). Deep sequencing using DNA samples obtained at 0, 6, 10, and 25 mo of age revealed that the percentage of cells with UPD7 increased constantly from 6% to 82% over 25 mo, and this increase coincided with a decrease in the percentage of cells with p.Ala1479Ser from 94% to nearly undetectable levels. We further screened for low-allele-frequency and rare SAMD9 variants in eight patients with Silver-Russel syndrome and maternal UPD7; however, none of the patients harbored such a variant. In conclusion, our case demonstrates that genetic findings can vary considerably in patients with MIRAGE syndrome and that a comprehensive diagnostic approach, including SNP array and deep sequencing, is important in such cases.

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A Rare Etiology of 46,XY Disorder of Sex Development and Adrenal Insufficiency: A Case of MIRAGE Syndrome Caused by Mutations in the SAMD9 Gene

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