OBSL1 – Three M Syndrome 2

Three M syndrome 2 (MONDO:0013039) is an autosomal recessive primordial growth disorder caused by biallelic pathogenic variants in OBSL1. Affected individuals present with disproportionate short stature, characteristic facial dysmorphism (prominent forehead, thick eyebrows, long philtrum), and musculoskeletal anomalies including barrel-shaped chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias.

Genetic evidence includes over 17 probands across 15 unrelated families harboring homozygous or compound heterozygous loss-of-function and splice-site OBSL1 variants, confirming autosomal recessive inheritance (PMID:37780995;25923536;33135300;19877176). The recurrent frameshift c.848del (p.Gly283AlafsTer54) was first identified in a consanguineous Pakistani pedigree (PMID:37780995). Segregation in multiple sibships further supports pathogenicity.

The variant spectrum spans >30 distinct OBSL1 alleles, predominantly nonsense, frameshift, and splice-site changes. Examples include c.35dup (p.Cys13fs) and c.1273dup (p.Thr425fs) in Indian patients (PMID:33135300) and c.848del (p.Gly283AlafsTer54) in the Pakistani kindred (PMID:37780995).

Functional studies demonstrate that OBSL1 loss-of-function perturbs growth factor signaling: patient fibroblasts exhibit dysregulated IGFBP2/IGFBP5 expression and impaired STAT5/MAPK/AKT activation upon GH or IGF1 stimulation (PMID:19877176;23018678). Murine Obsl1 knockout models recapitulate aspects of the human growth phenotype, consistent with a loss-of-function mechanism.

No conflicting reports dispute the OBSL1–3M2 association. The cumulative genetic and experimental data satisfy definitive ClinGen criteria for a gene–disease relationship.

Key Take-home: OBSL1 sequencing should be integrated into diagnostic workflows for individuals with primordial growth retardation and characteristic dysmorphism, enabling early genetic counseling and informed reproductive options.

References

• The Yale journal of biology and medicine • 2023 • Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias. PMID:37780995
• BMC Genomics • 2015 • Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome. PMID:25923536
• American journal of medical genetics. Part A • 2021 • Three M syndrome 2 in two Indian patients. PMID:33135300
• Human Mutation • 2010 • OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels. PMID:19877176
• Journal of Molecular Endocrinology • 2012 • Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. PMID:23018678

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