Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient’s methylation defects.
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We are grateful to the patients and their parents for their cooperation. We also thank Drs. Yoshihiko Hidaka, Masaru Nasuno, Daisuke Matsuoka, and Hiroyuki Sato for providing us with clinical data. This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) (18K06356), the National Center for Child Health and Development (2019A-1, 2019B-4), the Japan Agency for Medical Research and Development (AMED) (20ek0109373h0003), and the Takeda Science Foundation.
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The authors declare no competing interests.
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This study was approved by the Institutional Review Board Committee at the National Center for Child Health and Development (Committee’s Reference Number: 518) and performed after obtaining written informed consent to participate in this study from the patients or the patients’ parents.
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Hara-Isono, K., Matsubara, K., Hamada, R. et al. A patient with Silver-Russell syndrome with multilocus imprinting disturbance, and Schimke immuno-osseous dysplasia unmasked by uniparental isodisomy of chromosome 2. J Hum Genet 66, 1121–1126 (2021). https://doi.org/10.1038/s10038-021-00937-7