Skeletal dysplasia

Gene: LTBP3

Green List (high evidence)

Dental anomalies with short stature is recessive. Several cases reported - pathogenic variant almost missed because gene was tiered under AD mode of inheritance only.

Created: 14 Feb 2022, 10:35 p.m. | Last Modified: 14 Feb 2022, 10:35 p.m.

Panel Version: 2.170

spondylo-epi-(meta)-physeal dysplasias gp of SD. At least 3 cases reported.; Review on behalf of Tracy Lester

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

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Geleophysic dysplasia 3 617809; Dental anomalies and short stature 610216

Publications

• 19213025
• 25899461
• 25669657
• 19344874
• 8721563

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

I don't know

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 2:18 p.m. | Last Modified: 30 Jan 2023, 2:28 p.m.

Panel Version: 3.5

Comment on mode of inheritance: The mode of inheritance should be updated to Both mono- and bi-allelic at the next GMS review.

Created: 2 Mar 2022, 5:40 p.m. | Last Modified: 2 Mar 2022, 5:40 p.m.

Panel Version: 2.172

This gene originally had the mode of inheritance set to monoallelic based on the Geleophysic dysplasia 3 OMIM:617809 phenotype. This is supported by heterozygous variants in LTBP3 reported in PMID: 27068007 (McInerney-Leo et al 2016) - 2 cases with geleophysic dysplasia and 1 with acromelic dysplasia and PMID: 33082559 (Marzin et al 2021) - 2 cases with geleophysic dysplasia and 1 with acromelic dysplasia . Dental anomalies are not reported in either set of cases.

As Tracy Lester reports there are more than 3 cases of patients with both a dental phenotype and short stature and so the mode of inheritance should be updated to both mono- and bi-allelic.

PMID: 25899461 - Dugan et al 2015 - 2 sisters with homozygous truncating mutations (1 bp insertion) in LTBP3. Only this gene was analysed. They presented with oligodontia, short stature and mitral valve prolapse.

PMID: 25669657 - Huckert et al 2015 - report 4 families (3 consanguineous) with a phenotype of significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta. WES identified homozygous or compound het protein altering variants in LTBP3 in all patients (14 bp deletion, nonsense variant, splice site variant, 2 1bp deletions).

PMID:19344874 - Noor et al 2009 - consanguineous Pakistani family with oligodontia along with short stature in an autosomal-recessive fashion. A homozygous nonsense mutation, Y774X, within LTBP3 was identified.

PMID: 8721563 (abstract only accessed) and PMID: 19213025 report patients with a dental and skeletal phenotype but no genetic analysis.

Created: 2 Mar 2022, 5 p.m. | Last Modified: 2 Mar 2022, 5:39 p.m.

Panel Version: 2.171

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: LTBP3; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Comment on phenotypes: Dental anomalies and short stature 601216 associated with biallelic LTBP3 variants

Created: 6 Feb 2018, 10:40 a.m.

Associated with Geleophysic dysplasia 3 617809 phenotype in OMIM, not in G2P. At least 3 variants reported in 3 unrelated cases

Created: 6 Feb 2018, 10:39 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Geleophysic dysplasia 3 617809

Publications

• 27068007