Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients

Autor:	Tomoko Fuke, Akira Oka, Kanako Tanase-Nakao, Kazuhiko Nakabayashi, Tsutomu Ogata, Masayo Kagami, Junko Nishioka, Megumi Iwahashi-Odano, Yoshihiro Maruo, Akie Nakamura, Keiko Matsubara, Yoshiyuki Kobayashi, Seiji Sato, Hiroshi Suzumura, Satoshi Narumi, Maki Fukami, Yukihiro Hasegawa, Kazuki Yamazawa, Nobuyuki Murakami, Takanobu Inoue
Rok vydání:	2020
Předmět:	0301 basic medicine Epigenomics Heart Septal Defects Ventricular Male Cell Cycle Proteins Protein Tyrosine Phosphatase Non-Receptor Type 11 Pitt–Hopkins syndrome Multigene sequencing 030105 genetics & heredity Craniofacial Abnormalities Transcription Factor 4 IGF1R Hyperventilation Noonan syndrome Child Genetics (clinical) Growth Disorders Chromosome 7 (human) Genetics Adenosine Triphosphatases High-Throughput Nucleotide Sequencing Class Ia Phosphatidylinositol 3-Kinase Nephrocalcinosis Phenotype Child Preschool Female Adolescent DNA Copy Number Variations Biology SHORT syndrome Diagnosis Differential 03 medical and health sciences Chromosome 15 Chromosome 16 Metabolic Diseases Insulin-Like Growth Factor II Intellectual Disability Pitt-Hopkins syndrome parasitic diseases medicine Humans Abnormalities Multiple Floating-Harbor syndrome Molecular Biology Cyclin-Dependent Kinase Inhibitor p57 PLAG1 Functional analysis Silver–Russell syndrome Tumor Suppressor Proteins Research Facies DNA Methylation Uniparental Disomy medicine.disease Silver-Russell Syndrome 030104 developmental biology CDKN1C Floating–Harbor syndrome Mutation Hypercalcemia Chromosome 20 Developmental Biology Transcription Factors
Zdroj:	Clinical Epigenetics
ISSN:	1868-7083
Popis:	BackgroundSilver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However,IGF2,CDKN1C,HMGA2, andPLAG1mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype.ResultsMultigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely,PLAGL1:alt-TSS-DMR on chromosome 6,KCNQ1OT1:TSS-DMR on chromosome 11,MEG3/DLK1:IG-DMR on chromosome 14,MEG3:TSS-DMR on chromosome 14,SNURF:TSS-DMR on chromosome 15, andGNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%:IGF2in two patients,CDKN1C, andPLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%:IGF1Rabnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of theCDKN1Cvariant. The variants we detected inCDKN1CandPLAG1were the second and third variants leading to SRS, respectively. Our patients withCDKN1CandPLAG1variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmedIGF1Rabnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS.ConclusionsWe identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3295f8037dc14fdf09a00b3aad5a01a9 https://pubmed.ncbi.nlm.nih.gov/32546215 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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