Skeletal dysplasia

Gene: SEMA3A

Green List (high evidence)

Comment on list classification: There are three unrelated patients reported with biallelic SEMA3A variants and with multiple congenital anomalies including syndromic short stature and skeletal phenotypes. Hence, the MOI should be set as 'biallelic' and the gene should be promoted to green rating in the next GMS update.

Created: 4 Nov 2026, 3:29 p.m. | Last Modified: 4 Nov 2026, 3:29 p.m.

Panel Version: 10.35

Biallelic variants:
PMID:24124006 (2013) reported a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly. This patient was identified with compound heterozygous SEMA3A variants: 150 kb deletion on 7q21.11 affecting exon 1 of SEMA3A (paternal, healthy carrier) + de novo in-frame exon 9 mutation p.Phe316_Lys317-delinsThrSerSerAsnGlu.

PMID:28075028 (2017) reported the identification of a homozygous SEMA3A variant p.Arg203Ter in an 8 year old boy with a pattern of multiple congenital anomalies. The phenotype of this patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Hypogonadotrophic hypogonadism was also noted in the first week of life.

PMID:33369061 (2020) reported a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism, and anosmia and the patient harboured a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state.

Biallelic variants in this gene are not yet associated with phenotypes in OMIM, but associated with SEMA3A-related skeletal dysplasia in Gene2Phenotype (with 'definitive' rating on the DD panel).

Monoallelic variants:
There is sufficient evidence available for the association of monoallelic SEMA3A variants with hypogonadotropic hypogonadism/ Kallmann syndrome despite some of the patients harbouring variants from additional KS genes. Monoallelic SEMA3A variants are associated with hypogonadotropic hypogonadism 16 with or without anosmia in OMIM (MIM #614897) and the record was last accessed on 04 November 2026. However, none of the reported patients displayed skeletal phenotypes.

Animal models:
PMID: 8849723 (1996) generated mutant mice lacking semaphorin III that exhibited reduced cortical neuropil, abnormally oriented neuronal processes, skeletal malformations and, in the few surviving beyond the first postnatal days, pronounced right ventricular hypertrophy and right atrial dilation, whereas heterozygous mice appeared normal.
Sources: Literature

Created: 4 Nov 2026, 3:24 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
skeletal dysplasia, MONDO:0018230

Publications

• 8849723
• 22416012
• 22927827
• 24124006
• 28075028
• 32060892
• 33369061