Is autosomal recessive Silver-Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum?

• Published in: American journal of medical genetics. Part A 2011-06, Vol.155A (6), p.1236-1245
• Main Authors: Akawi, Nadia A., Ali, Bassam R., Hamamy, Hanan, Al-Hadidy, Azmy, Al-Gazali, Lihadh
• Format: Article
• Language: English
• Subjects: Asymmetry; Base Sequence; Biological and medical sciences; CUL7; Cullin Proteins - genetics; Cytoskeletal Proteins - genetics; Differentiation; DNA sequencing; Dwarfism - genetics; Dwarfism - pathology; Gene deletion; Genes, Recessive; Growth rate; Heredity; Humans; Intellectual Disability - genetics; Intellectual Disability - pathology; Jordan; Limbs; Medical genetics; Medical sciences; Microarray Analysis; Molecular Sequence Data; Muscle Hypotonia - genetics; Muscle Hypotonia - pathology; Mutation - genetics; Nonsense mutation; OBSL1; Phenotype; Polymorphism, Single Nucleotide - genetics; Sequence Analysis, DNA; Silver-Russel syndrome; Silver-Russell Syndrome - classification; Silver-Russell Syndrome - genetics; Silver-Russell Syndrome - pathology; Single-nucleotide polymorphism; Spine - abnormalities; Spine - pathology; three M syndrome; United Arab Emirates
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.34009

Intrauterine growth retardation (IUGR) is a nonspecific finding that occurs in approximately 0.17% of all live‐births. However, IUGR can also be a significant feature of many recognized genetic syndromes including Silver–Russel syndrome (SRS), Three M syndrome (3‐M), Dubowitz syndrome, and Mulibrey nanism. Differentiation of 3‐M syndrome from autosomal recessive SRS has been difficult because of the phenotypic variability of the latter. Limb length asymmetry is seen in over half of those with autosomal recessive SRS, but not in individuals with 3‐M syndrome. Characteristic radiologic findings of 3‐M syndrome are not present in SRS. We used single nucleotide polymorphism (SNP) microarrays to investigate the cause of phenotypic features of SRS that shows autosomal recessive inheritance in three consanguineous families, two from United Arab Emirates (UAE), and one from Jordan. The mapped regions contained CUL7 and OBSL1, the genes that have recently been shown to cause 3‐M syndrome. Subsequently, direct DNA sequencing of CUL7 and OBSL1 genes revealed novel mutations in both genes including two mutations in OBSL1 [c.1119G>C (p.W373C) and c.681_682delinsTT (p.Q228X)], and a nonsense mutation in CUL7 [c.203G>A (p.W68X)]. In addition, a six nucleotide deletion in CUL7 [c.649_654delAGCCGC (p.217_218delSR)] was found in a consanguineous family from UAE that had the typical features of 3‐M. As a result of these findings, we question the identity of the autosomal recessive SRS and suggest that all apparently recessive SRS families should be tested for mutations in CUL7 and OBSL1. © 2011 Wiley‐Liss, Inc.