Clefting

Gene: RSPO2

Green List (high evidence)

Comment on list classification: There are four unrelated families reported with biallelic RSPO2 variants and with Tetraamelia syndrome and these patients presented with cleft lip/ palate. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 3 Nov 2026, 1:31 p.m. | Last Modified: 3 Nov 2026, 1:31 p.m.

Panel Version: 7.22

PMID:29769720 (2018) reported eleven affected individuals from five different families displaying severe developmental limb defects. Four affected foetuses from a consanguineous Turkish family (family 1) presented with radial ray deficiency with humeral involvement, absence of tibiae with or without femoral deficiency, and absence of digits on the preaxial side. The seven affected foetuses from four other families (families 2-5) presented with complete absence of four limbs, lung hypo/aplasia, cleft lip/ palate and labioscrotal fold aplasia, all characteristic of Tetraamelia syndrome (TETAMS). The family with humerofemoral hypoplasia with radiotibial ray deficiency (family 1) was identified with homozygous RSPO2 missense variant (p.Arg64Cys), while the families with Tetraamelia syndrome were identified with homozygous RSPO2 nonsense variants (p.Gln70Ter in family 2 and p.Glu137Ter in family 4), homozygous RSPO2 frmeshift variant (p.Gly42val fs*49 in family 5) or biallelic 154kb deletion spanning intron 5 and exon 6 of RSPO2 (family 3).

There is also animal models and functional evidence available from PMIDs 29769720 & 32457899.

This gene has already been associated with relevant phenotypes in OMIM (MIMs #618021 & #618022) and Gene2Phenotype (with 'strong' rating on the DD panel), and these records were last accessed on 03 November 2026.

Created: 3 Nov 2026, 1:28 p.m. | Last Modified: 3 Nov 2026, 1:28 p.m.

Panel Version: 7.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Tetraamelia syndrome 2, OMIM:618021; tetraamelia syndrome 2, MONDO:0060732; ?Humerofemoral hypoplasia with radiotibial ray deficiency, OMIM:618022; humerofemoral hypoplasia with radiotibial ray deficiency, MONDO:0060733

Publications

• 29769720
• 32457899