GSC2

Chr 22

goosecoid homeobox 2

Also known as: GSCL

NCBI Gene: 2928 ENSG00000063515 UniProt: O15499 OMIM: 601845

GSC2 encodes a homeodomain-containing transcription factor that may regulate its own transcription and bind specific DNA sequences during development. The gene is located in the 22q11 deletion region associated with velocardiofacial syndrome and DiGeorge syndrome, which are characterized by conotruncal heart defects, craniofacial anomalies, and learning disabilities. These syndromes follow an autosomal dominant inheritance pattern due to hemizygous deletions, and the gene shows low constraint to loss-of-function variation in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Goosecoidlike (GSCL), a homeodomain-containing gene, resides in the critical region for VCFS/DGS on 22q11. Velocardiofacial syndrome (VCFS) is a developmental disorder characterized by conotruncal heart defects, craniofacial anomalies, and learning disabilities. VCFS is phenotypically related to DiGeorge syndrome (DGS) and both syndromes are associated with hemizygous 22q11 deletions. Because many of the tissues and structures affected in VCFS/DGS derive from the pharyngeal arches of the developing embryo, it is believed that haploinsufficiency of a gene involved in embryonic development may be responsible for its etiology. The gene is expressed in a limited number of adult tissues, as well as in early human development. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.91

Clinical Summary— GSC2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.91LOEUF

pLI 0.004

Z-score -0.35

OE 1.24 (0.50–1.91)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.55Z-score

OE missense 1.20 (0.99–1.47)

69 obs / 57.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.24 (0.50–1.91)

0≤0.351.4

Missense OE?1.20 (0.99–1.47)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 3 / 2.4Missense obs/exp: 69 / 57.3Syn Z: 0.13

This gene — mechanism propensity

0.6550th %ile

GOF

0.5562th %ile

LOF

0.57top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.