HMGA2 – Silver-Russell Syndrome 5

Silver-Russell syndrome 5 (SRS5) is an autosomal dominant growth disorder characterized by intrauterine growth restriction, postnatal short stature, macrocephaly at birth, feeding difficulties, triangular facial gestalt and body asymmetry. Key dysmorphic features include prominent forehead, hypertelorism, epicanthus, micrognathia, brachydactyly and clinodactyly of the 5th finger. Pathogenic variants in HMGA2, a chromatin architectural protein that regulates IGF2 transcription, have recently been implicated in SRS5.

Genetic evidence includes 11 unrelated probands harboring HMGA2 variants (2 nonsense, 2 frameshift, 1 missense, 2 splice/intronic) across five families, consistent with autosomal dominant inheritance and variable expressivity ([PMID:25809938]; [PMID:32421827]; [PMID:38516887]). The variant spectrum comprises splicing mutations (e.g., c.283-6_283del), canonical splice‐site disruption (c.111+1G>T), truncating alleles (c.49G>T, c.52C>T, c.144del, c.145del) and a recurrent missense allele c.166A>G (p.Lys56Glu).

Segregation analysis demonstrates co-segregation of HMGA2 variants with SRS phenotype in five multiplex families, including a heterozygous mother–child pair and a homozygous sib pair with more severe growth restriction ([PMID:25809938]; [PMID:32421827]; [PMID:38516887]).

Functional studies support a loss-of-function mechanism: patient-derived nonsense and frameshift alleles exhibit absent or reduced nuclear localization. Knockin mouse models recapitulating the c.166A>G missense (Hmga2K56E) and a null allele (Hmga2Ter76) display growth restriction and pygmy phenotypes concordant with human SRS5 ([PMID:38516887]).

No studies have yet refuted the HMGA2–SRS5 association, though a variant of uncertain significance in a single case underscores the need for variant‐specific functional assessment ([PMID:38789914]).

In summary, multiple unrelated probands, consistent segregation, and concordant murine models establish a strong gene–disease relationship. HMGA2 testing is recommended in SRS patients negative for 11p15 alterations and matUPD7. Key Take-home: HMGA2 haploinsufficiency is a clinically actionable cause of SRS5, informing diagnosis and genetic counseling.

References

• Journal of human genetics • 2015 • A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype. PMID:25809938
• The Journal of clinical endocrinology and metabolism • 2020 • HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence. PMID:32421827
• JCI Insight • 2024 • Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome. PMID:38516887

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