Skeletal dysplasia

Gene: TMEM67

I don't know

polydactyly-syndactyly-triphalangism SD gp - ? Occasionally polydactyly - none described in COACH, JS6, rare in MS3. amber - only polydactyly and this is appears rare, not isolated; Review on behalf of Tracy Lester/Michael Oldridge

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
COACH syndrome 216360; Joubert syndrome 6 610688; Meckel syndrome 3 607361; {Bardet-Biedl syndrome 14, modifier of} 615991

I don't know

Comment on list classification: After consultation with the Genomics England clinical team demoting this gene to red as the skeletal phenotype is not strong.

Created: 15 Nov 2019, 2:49 p.m. | Last Modified: 15 Nov 2019, 2:49 p.m.

Panel Version: 1.215

Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361).

RHYNS syndrome - 1 case:

PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents.

PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done.

Meckel syndrome 3 - 3 out of 22 cases show polydactyly:

PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families.

PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.

Created: 16 Jul 2019, 3:46 p.m. | Last Modified: 13 Nov 2019, 4:07 p.m.

Panel Version: 1.204

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: TMEM67; Initial rating suggestion: amber

Created: 6 Mar 2019, 11:37 a.m.

Comment when marking as ready: Associated with phenotypes in G2P. Numerous variants reported in these phenotypes.

Created: 12 Jul 2016, 2:05 p.m.

Comment on phenotypes: Variants also reported in Nephronophthisis 11 613550, which is not relevant to this panel

Created: 12 Jul 2016, 2:04 p.m.

Green List (high evidence)

Tier 2

Created: 17 Jun 2016, 8:09 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
COACH syndrome 216360; Joubert syndrome 6 610688; Meckel syndrome 3 607361; Nephronophthisis 11 613550; {Bardet-Biedl syndrome 14, modifier of} 615991

Variants in this GENE are reported as part of current diagnostic practice