Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions

Abstract

The main features of Silver-Russell syndrome (SRS) are pre-and postnatal growth restriction and a characteristic small, triangular face. SRS is also accompanied by other dysmorphic features including fifth finger clinodactyly and skeletal asymmetry. The disorder is clinically and genetically heterogeneous, and various modes of inheritance and abnormalities involving chromosomes 7, 8, 15, 17, and 18 have been associated with SRS and SRS-like cases. However, only chromosomes 7 and 17 have been consistently implicated in patients with a strict clinical diagnosis of SRS. Two cases of balanced translocations with breakpoints in 17q23.3-q25 and two cases with a hemizygous deletion of the chorionic somatomammatropin gene (CSH1) on 17q24.1 have been associated with SRS, strongly implicating this region. Maternal uniparental disomy for chromosome 7 (mUPD(7)) occurs in up to 10% of SRS patients, with disruption of genomic imprinting underlying the disease status in these cases. Recently, two SRS patients with a maternal duplication of 7p11.2-p13, and a single proband with segmental mUPD for the region 7q31-qter, were described. These key patients define two separate candidate regions for SRS on both the p and q arms of chromosome 7. Both the 7p11.2-p13 and 7q31-qter regions are subject to genomic imprinting and the homologous regions in the mouse are associated with imprinted growth phenotypes. This review provides an overview of the genetics of SRS, and focuses on the newly defined candidate regions on chromosome 7. The analyses of imprinted candidate genes within 7p11.2-p13 and 7q31-qter, and gene candidates on distal 17q, are discussed. (J Med Genet 2001;38:810-819) Keywords: Silver-Russell syndrome; imprinting; mUPD(7); candidates

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

“…The prognosis for SRS is favourable, but for a diminished adult size. (20,21) Usually, diagnosis of SRS is established when growth retardation, facial dysmorphism and one or more of the minor features are present. Diagnosis may be subjective, however, and SRS could comprise different disorders with clinically similar phenotypes, or could result from disruption of different components of a single pathway.…”

“…However, there are families in which genetic transmission of the disease has been observed, and predominant maternal transmission in some of them had suggested that genomic imprinting could be involved. (21) In addition, specific chromosomal abnormalities have been described in some cases, involving different chromosomes. For example, several SRS families were identified with maternal duplications of chromosome 11p15, but without any apparent genetic mutations.…”

Silver-Russell syndrome in a girl born after in vitro fertilization: partial hypermethylation at the differentially methylated region of PEG1/MEST

“…Silver-Russell syndrome (SRS) is a congenital developmental disorder characterized by pre-and postnatal growth failure, body asymmetry, relative macrocephaly, triangular face, and fifth-finger clinodactyly [1]. Precocious puberty is also occasionally observed in this condition.…”

“…The possibility of unmasking of a recessive allele(s) by isodisomy is unlikely, because both isodisomy and heterodisomy have been found in SRS with no common isodisomic region [2]. Furthermore, molecular studies in several key patients have suggested two separate candidate regions for SRS, 7p11.2-p13 [3] and 7q31-qter [4], and several candidate genes such as GRB10 (growth factor receptor-bound protein 10) on 7p12 and PEG1/MEST (paternally expressed gene 1/mesoderm-specific transcript) on 7q32.2 have been identified [1], although the gene(s) responsible for SRS has not been identified to date. In addition, recent studies have shown hypomethylation of the differentially methylated region (DMR) located upstream of H19 (H19-DMR) in a considerable fraction of SRS patients, providing further support for the relevance of imprinting failure in SRS [5].…”

“…Precocious puberty is also occasionally observed in this condition. Since maternal uniparental disomy for chromosome 7 (mUPD7) has been identified in 7-10% of patients with SRS, this implies the involvement of a single or plural imprinted genes on chromosome 7 in the development of SRS [1]. The possibility of unmasking of a recessive allele(s) by isodisomy is unlikely, because both isodisomy and heterodisomy have been found in SRS with no common isodisomic region [2].…”