Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects

• Published in: Clinical epigenetics Vol. 9; no. 1; p. 52
• Main Authors: Inoue, Takanobu, Nakamura, Akie, Fuke, Tomoko, Yamazawa, Kazuki, Sano, Shinichiro, Matsubara, Keiko, Mizuno, Seiji, Matsukura, Yoshika, Harashima, Chie, Hasegawa, Tatsuji, Nakajima, Hisakazu, Tsumura, Kumi, Kizaki, Zenro, Oka, Akira, Ogata, Tsutomu, Fukami, Maki, Kagami, Masayo
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central 15.05.2017; BMC
• Subjects: 4p microdeletion syndrome; Array comparative genomic hybridization; Birth weight; Brachydactyly; Child; Child, Preschool; Chromosome 7; Comparative Genomic Hybridization - methods; Congenital diseases; Copy number; Coronary artery disease; Defects; Developmental Disabilities - diagnosis; Developmental Disabilities - genetics; DNA Copy Number Variations; DNA Methylation; Epigenesis, Genetic; Female; Genes; Genetic Heterogeneity; Genomes; Genomic Imprinting; Genotype & phenotype; Heart diseases; Heart Diseases - congenital; Heart Diseases - diagnosis; Heart Diseases - genetics; Humans; Hybridization analysis; Infant; Male; Mosaic trisomy 18; Mutation; Netchine-Harbison clinical scoring system; Pathogenic copy number variation; Short Report; Silver; Silver-Russell syndrome; Silver-Russell Syndrome - genetics; Studies; Trisomy; Uniparental disomy; Xenografts; Young Adult; Array comparative genomic hybridization; Pathogenic copy number variation; 4p microdeletion syndrome; Silver-Russell syndrome; Mosaic trisomy 18; Netchine-Harbison clinical scoring system; 19q13.11 deletion syndrome; Williams syndrome
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-017-0350-6

Silver-Russell syndrome (SRS) is a rare congenital disorder characterized by pre- and postnatal growth failure and dysmorphic features. Recently, pathogenic copy number variations (PCNVs) and imprinting defects other than hypomethylation of the -differentially methylated region (DMR) and maternal uniparental disomy chromosome 7 have been reported in patients with the SRS phenotype. This study aimed to clarify the frequency and clinical features of patients with SRS phenotype caused by PCNVs. We performed array comparative genomic hybridization analysis using a catalog array for 54 patients satisfying the Netchine-Harbison clinical scoring system (NH-CSS) (SRS-compatible) and for 28 patients presenting with three NH-CSS items together with triangular face and/or fifth finger clinodactyly and/or brachydactyly (SRS-like) without abnormal methylation levels of 9 DMRs related to known imprinting disorders. We then investigated the clinical features of patients with PCNVs. Three of the 54 SRS-compatible patients (5.6%) and 2 of the 28 SRS-like patients (7.1%) had PCNVs. We detected 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, and 3.77-4.00 Mb deletion in 19q13.11-12 in SRS-compatible patients, and 1.41-1.97 Mb deletion in 7q11.23 in both SRS-like patients. Congenital heart diseases (CHDs) were identified in two patients and moderate to severe global developmental delay was observed in four patients. Of the patients in our study, 5.6% of SRS-compatible and 7.1% of SRS-like patients had PCNVs. All PCNVs have been previously reported for genetic causes of contiguous deletion syndromes or mosaic trisomy 18. Our study suggests patients with PCNVs, who have a phenotype resembling SRS, show a high tendency towards CHDs and/or apparent developmental delay.