Limb disorders

Gene: SMO

Green List (high evidence)

The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 5 Mar 2022, 8:17 p.m. | Last Modified: 5 Mar 2022, 8:17 p.m.

Panel Version: 2.67

Comment on mode of inheritance: Leaving MOI has monoallelic just now, but with recommendation for updating to BOTH monoallelic and biallelic at the next review, due to additional biallelic cases now reported.

Created: 19 Jan 2021, 11:55 a.m. | Last Modified: 19 Jan 2021, 11:55 a.m.

Panel Version: 2.29

As reported by expert reviewer Le et al (PMID:32413283) report biallelic variants in 7 individuals from 5 families that present with a wide spectrum of phenotypes in a condition that is distinct from Curry-Jones syndrome.
Phenotypes observed include Postaxial polydactyly (7/7), syndactyly (5/7, 3 families), chest and rib abnormalities (2/7, 2 families), and Gelastic epilepsy, Hypothalamic hamartoma, Microcephaly, Dysmorphic facial features, Cardiac defect, Hirschsprung disease all in various proportions of patients. Variants types found include missense, small deletion leading to truncated protein, and whole gene deletion. The authors propose a loss of function mechanism for all variants. Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction.

Created: 19 Jan 2021, 11:52 a.m. | Last Modified: 19 Jan 2021, 11:52 a.m.

Panel Version: 2.26

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
postaxial polydactyly MONDO:0020927; Microcephaly HP:0000252; congenital heart disease MONDO:0005453; Hirschsprung disease MONDO:0018309

Publications

• 32413283

Green List (high evidence)

Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
This is a distinct condition from Curry-Jones syndrome, which is caused by a recurrent somatic missense variant.

Created: 4 Jun 2020, 11:20 p.m. | Last Modified: 4 Jun 2020, 11:20 p.m.

Panel Version: 2.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly, congenital heart disease, polydactyly, aganglionosis

Publications

• 32413283

Comment on mode of inheritance: Changed MOI from 'Other' in order to capture variants within this gene in our current tiering pipeline.

Created: 5 Nov 2018, 9:05 a.m.

Comment on list classification: Updated rating from Red to Green: sufficient unrelated cases of syndactyly and/or preaxial polydactyly in Curry-Jones patients for inclusion on panel.

Created: 16 Oct 2018, 2:08 p.m.

Comment on mode of inheritance: Somatic mosaic.

Created: 16 Oct 2018, 2:07 p.m.

Added 'somatic' tag.

Created: 16 Oct 2018, 2:06 p.m.

PMID:27236920 (Twigg et al, 2016) analysed 10 unrelated patients with Curry-Jones syndrome including 6 previously reported patients. They identified somatic mosaicism for the identical L412F variant in SMO in 8 of the patients. The patients all showed cutaneous syndactyly and/or preaxial polydactyly.

Created: 2 Oct 2018, 2:23 p.m.

Comment on mode of pathogenicity: Somatic mosaicism.

Created: 2 Oct 2018, 2:21 p.m.

Added 'mosaicism' tag based on PMID:27236920, DD-G2P and OMIM information.

Created: 2 Oct 2018, 2:20 p.m.