ESPE Abstracts (2018) 89 RFC15.2

Molecular and Clinical Analyses of Two UPD(16)mat Patients Detected by Screening of 94 Silver-Russell Syndrome Patients without Known Etiology

Takanobu Inouea,b, Hideaki Yagasakic, Junko Nishiokad, Akie Nakamuraa,e, Keiko Matsubaraa, Satoshi Narumia, Kazuhiko Nakabayashif, Kazuki Yamazawaa, Tomoko Fukea, Akira Okab, Tsutomu Ogataa,g, Maki Fukamia & Masayo Kagamia


aDepartment of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; bDepartment of Pediatrics, University of Tokyo, Tokyo, Japan; cDepartment of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan; dDepartment of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan; eDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan; fDepartment of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan; gDepartment of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan


Background: Maternal uniparental disomy of chromosome 16 (UPD(16)mat) is defined as the presence of two homologous chromosomes 16 inherited from only the mother. To our knowledge, 49 live-born UPD(16)mat patients without chromosomal abnormalities other than that in chromosome 16 have been reported. UPD(16)mat patients presented with non-specific clinical features such as preterm birth, growth retardation, congenital heart diseases (CHDs) and hypospadias. Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Hypomethylation of the H19/IGF2:IG-differentially methylated region (DMR) at the 11p15 imprinted region (H19-hypo) and maternal uniparental disomy of chromosome 7 (UPD(7)mat) are major genetic causes of SRS. Recently, a patient with UPD(16)mat presenting SRS phenotype was reported. However, the prevalence of UPD(16)mat in SRS patients and the phenotypic difference between UPD(16)mat and SRS have been poorly documented.

Methods: We studied 94 SRS patients without known etiology. Sixty-three out of 94 patients satisfied Netchine-Harbison clinical scoring system (NH-CSS) criteria (SRS-compatible) and the remaining 31 patients met three NH-CSS criteria together with triangular face, fifth finger clinodactyly and/or brachydactyly. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-DMR and subsequently performed microsatellite, single-nucleotide polymorphism array and exome analyses in patients with a hypo-methylated ZNF597:TSS-DMR.

Results: We identified two patients (3.2%) with a mixture of maternal iso- and heterodisomy of chromosome 16 in the SRS-compatible group. Both patients exhibited preterm birth, growth failure, and mild intellectual disability. The male patient had ventricular septal defect and hypospadias. Whole exome sequencing detected no gene mutations related to their phenotypes.

Discussion: Our study suggests that UPD(16)mat constitutes a rare but important underlying factor for SRS. We compared the clinical findings between patients with UPD(16)mat in the literature and this report and previously reported patients with H19-hypo or UPD(7)mat. The median of gestational ages in UPD(16)mat was earlier than in H19-hypo and UPD(7)mat. The frequency of SGA was significantly lower in UPD(16)mat than in both H19-hypo and UPD(7)mat, and that of CHDs was significantly higher in UPD(16)mat than in both H19-hypo and UPD(7)mat. Genetic testing of UPD(16)mat should be considered for etiology-unknown SRS cases with preterm birth and CHDs, even if they are not born SGA.