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. 2017 May 15:9:52.
doi: 10.1186/s13148-017-0350-6. eCollection 2017.

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

Takanobu Inoue  1   2 , Akie Nakamura  1 , Tomoko Fuke  1 , Kazuki Yamazawa  1 , Shinichiro Sano  1 , Keiko Matsubara  1 , Seiji Mizuno  3 , Yoshika Matsukura  4 , Chie Harashima  4 , Tatsuji Hasegawa  5 , Hisakazu Nakajima  5 , Kumi Tsumura  6 , Zenro Kizaki  7 , Akira Oka  2 , Tsutomu Ogata  1   8 , Maki Fukami  1 , Masayo Kagami  1
Affiliations

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

Takanobu Inoue et al. Clin Epigenetics. .

Abstract

Background: 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 H19-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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 19q13.11 deletion syndrome; 4p microdeletion syndrome; Array comparative genomic hybridization; Mosaic trisomy 18; Netchine-Harbison clinical scoring system; Pathogenic copy number variation; Silver-Russell syndrome; Williams syndrome.

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Figures

Fig. 1
Fig. 1
The flowchart of inclusion criteria. From 2002 to 2016, 292 patients were referred to us for genetic diagnosis of Silver-Russell syndrome (SRS). We studied 82 patients with SRS clinical features, and no abnormal methylation levels for 9 differentially methylated regions related to known imprinting disorders.
Fig. 2
Fig. 2
Array comparative genomic hybridization profiles of the five patients with pathogenic copy number variations. a Patient 1 (SRS-compatible, 4p16.3 deletion). b Patient 2 (SRS-compatible, mosaic trisomy 18). c Patient 3 (SRS-compatible, 19q13.11-12 deletion). d Patient 4 (SRS-like, 7q11.23 deletion). e Patient 5 (SRS-like, 7q11.23 deletion). The black, red, and green dots denote signals indicative of the normal, increased (> + 0.4), and decreased (<–0.8) copy numbers, respectively
Fig. 3
Fig. 3
Photographs of patients with pathogenic copy number variations. a Patient 3 (SRS-compatible, 19q13.11 deletion syndrome). The patient had cutis aplasia over the occiput, which is characteristic of 19q13.11 deletion syndrome. b Patient 4 (SRS-like, Williams syndrome)
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