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

• Published in: Clinical epigenetics 2020-06, Vol.12 (1), p.86-86, Article 86
• Main Authors: Inoue, Takanobu, Nakamura, Akie, Iwahashi-Odano, Megumi, Tanase-Nakao, Kanako, Matsubara, Keiko, Nishioka, Junko, Maruo, Yoshihiro, Hasegawa, Yukihiro, Suzumura, Hiroshi, Sato, Seiji, Kobayashi, Yoshiyuki, Murakami, Nobuyuki, Nakabayashi, Kazuhiko, Yamazawa, Kazuki, Fuke, Tomoko, Narumi, Satoshi, Oka, Akira, Ogata, Tsutomu, Fukami, Maki, Kagami, Masayo
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Adenosine Triphosphatases - genetics; Adolescent; Analysis; Asymmetry; Bone dysplasia; Cell Cycle Proteins - genetics; Child; Child, Preschool; Chromosomal proteins; Chromosome 11; Chromosome 14; Chromosome 15; Chromosome 16; Chromosome 20; Chromosome 6; Chromosome 7; Chromosomes; Class Ia Phosphatidylinositol 3-Kinase - genetics; Copy number; Craniofacial Abnormalities - diagnosis; Craniofacial Abnormalities - genetics; Cyclin-Dependent Kinase Inhibitor p57 - genetics; Development and progression; Diagnosis, Differential; DNA Copy Number Variations - genetics; DNA Methylation - genetics; DNA sequencing; Dysplasia; Epigenomics - methods; Etiology; Etiology (Medicine); Facies; Female; Gene mutation; Genes; Genetic aspects; Genetic research; Genetic screening; Genetic testing; Genomic imprinting; Genotype & phenotype; Gestational age; Growth Disorders - diagnosis; Growth Disorders - genetics; Heart Septal Defects, Ventricular - diagnosis; Heart Septal Defects, Ventricular - genetics; High-Throughput Nucleotide Sequencing - methods; Humans; Hypercalcemia - diagnosis; Hypercalcemia - genetics; Hyperventilation - diagnosis; Hyperventilation - genetics; Immunoglobulins; Insulin-like growth factor II; Insulin-Like Growth Factor II - genetics; Intellectual Disability - diagnosis; Intellectual Disability - genetics; KCNQ1OT1 protein; Male; Medical research; Metabolic Diseases - diagnosis; Metabolic Diseases - genetics; Methylation; Mutation; Nephrocalcinosis - diagnosis; Nephrocalcinosis - genetics; Noonan Syndrome - diagnosis; Noonan Syndrome - genetics; Noonan's syndrome; Pathogenicity; Patients; Phenotype; Phenotypes; Potassium channels (voltage-gated); Preadipocyte factor 1; Protein expression; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Proteins; Sequence analysis; Silver-Russell Syndrome - diagnosis; Silver-Russell Syndrome - etiology; Silver-Russell Syndrome - genetics; Skeleton; Transcription Factor 4 - genetics; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; Uniparental disomy; Uniparental Disomy - genetics
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-020-00865-x

Silver-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, and PLAG1 mutations 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. Multigene 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, and GNAS 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%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, 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. We identified nine patients (9.8%) with