Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver-Russell syndrome.

Silver-Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient's intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7 Mb duplication at 15q11.2-q13.1 encompassing the Prader-Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS.

Screening for imprinting disorders in 58 patients with clinically diagnosed idiopathic short stature.

Objectives Imprinted genes have important roles for normal growth and development. Imprinting disorders (IDs) such as Silver-Russell syndrome and Temple syndrome are rare diseases that typically cause short children born small for gestational age (SGA). However, some patients with short stature (SS) caused by IDs were born non-SGA. To date, the contribution of IDs to idiopathic short stature (ISS) has been poorly investigated. The aim of this study was to clarify the contribution of IDs to ISS. Methods We conducted methylation analysis for 10 differentially methylated regions using pyrosequencing to detect known IDs in 58 patients (31 male and 27 female children, height standard deviation score -4.2 to -2.0) carrying a clinical diagnosis of ISS. Results We identified no patient with IDs among these patients with ISS. Conclusions These results indicate that IDs are rare in patients having ISS, and that imprinted genes affect fetal growth more than postnatal growth. Because patients with IDs born non-SGA usually have clinical features characteristic of each ID, in addition to SS, the patients with ISS as a clinical diagnosis may not be associated with IDs. It is unlikely that cases clinically diagnosed with ISS are caused by IDs leading to growth failure.