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SOX11 – Intellectual disability, autosomal dominant 27

SOX11 is a high-mobility group (HMG) box transcription factor critical for early embryogenesis and neurogenesis. Heterozygous variants of SOX11 have been implicated in a distinct autosomal dominant neurodevelopmental disorder characterized by intellectual disability, growth deficiency, microcephaly, and additional congenital anomalies (MONDO:0014376).

Initial evidence from a 2016 cohort identified ten unrelated individuals with SOX11 loss-of-function alterations, including seven de novo chromosome 2p25 deletions encompassing SOX11 and three de novo point mutations (c.87C>A (p.Cys29Ter), c.150G>T (p.Lys50Asn), c.359C>A (p.Pro120His)), all presenting with microcephaly, developmental delay, dysmorphic features, and hypoplastic nails (PMID:26543203). Xenopus knockdown of Sox11 recapitulated microcephaly in vivo, supporting haploinsufficiency.

A 2022 multi-patient study described three unrelated Chinese probands with variable phenotypes—global developmental delay, intellectual disability, short stature, microcephaly, facial dysmorphism, and cryptorchidism. Whole-exome sequencing revealed three novel de novo SOX11 variants: c.337T>C (p.Tyr113His), c.425C>G (p.Ala142Gly), and c.820A>T (p.Lys274Ter) (PMID:35938035).

Luciferase reporter assays demonstrated that the two missense variants significantly impaired transcriptional activation of the SOX11 target gene GDF5, confirming a functional deficit. Combined with the in vivo morpholino studies, these data establish SOX11 haploinsufficiency as the disease mechanism.

The cumulative genetic and experimental findings meet ClinGen criteria for a Strong gene–disease association. SOX11 sequencing should be incorporated into diagnostic gene panels for intellectual disability, facilitating accurate diagnosis, genetic counseling, and exploration of targeted interventions.

References

  • Journal of medical genetics • 2016 • Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome. PMID:26543203
  • Frontiers in genetics • 2022 • Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9. PMID:35938035

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

13 unrelated patients with de novo SOX11 variants or deletions and concordant functional data ([PMID:26543203], [PMID:35938035])

Genetic Evidence

Strong

Ten probands with de novo SOX11 deletions or truncating variants and three additional de novo missense variants in a separate cohort support autosomal dominant inheritance ([PMID:26543203], [PMID:35938035])

Functional Evidence

Moderate

Xenopus Sox11 knockdown models recapitulate microcephaly and human SOX11 missense variants impair GDF5 transcription in luciferase assays ([PMID:26543203], [PMID:35938035])