Skeletal dysplasia

Gene: MIA3

Green List (high evidence)

Comment on phenotypes: OMIM phenotype (?Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269) accessed on 16 Dec 2025

Created: 2 Jan 2026, 11 a.m. | Last Modified: 2 Jan 2026, 11 a.m.

Panel Version: 8.30

Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update - at least 6 unrelated individuals with biallelic variants in this gene and skeletal dysplasia. Supported by animal models.

Created: 16 Dec 2025, 12:55 p.m. | Last Modified: 16 Dec 2025, 1:15 p.m.

Panel Version: 8.26

At least four additional cases with biallelic variants in this gene and a severe skeletal dysplasia.

PMID: 33778321 (2021) - Indian family with third degree consanguinity, with a history of three pregnancy terminations due to clinical suspicion of lethal osteogenesis imperfecta and one full‐term pregnancy. The proband was a fetus with a lethal skeletal dysplasia and fetal hydrops. WES revealed a homozygous frameshift c.2770_2773del, p.(Leu924Serfs*) in MIA3 (also known as TANGO1). Segregation analysis confirmed both parents are heterozygote carriers.

PMID: 40948380 (2025) - Homozygous c.354+2T>G (p.Val90_Asp118del) was identified in an 3 year old male born to Iranian consanguineous parents. The phenotype consisted of short limbs, short stature, hypotonia at birth and delayed walking.

PMID: 40119123 (2025) - Homozygous c.354+2T>G p.(Val90_Asp118del) in a 5 year old Egyptian male and homozygous c.113G>T p.(Cys38Phe) in a second Egyptian patient aged 1 year and 9 months old with severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, dentinogenesis imperfecta. Previously reported extra-skeletal manifestations (hearing loss, retinopathy, hydronephrosis, microalbuminuria, diabetes, primary obesity, and intellectual disability) were not observed. Both individuals were born to consanguineous parents.

PMID: 40130161 (2025) - Homozygous c.2768T>G, p.(Leu923*) was detected in a fetus from a Slovenian family who presented with short bones of extremities (7 percentile), fibular aplasia, bilateral radial aplasia, tibial aplasia, hypoplastic nasal bone, delayed ossification, and congenital contractures.

MIA3 KO mice show neonatal lethality due to insufficient bone mineralization (PMID: 21606205). Skeletal phenotype also seen in dogs with homozygous splice variant (PMID: 34680893).

Created: 16 Dec 2025, 12:54 p.m. | Last Modified: 16 Dec 2025, 1:14 p.m.

Panel Version: 8.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Odontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269

Publications

• 32101163
• 33778321
• 40948380
• 40119123
• 40130161
• 21606205
• 34680893

Red List (low evidence)

Comment on list classification: Promoting this gene from grey to red based on 1 family reported so far.

Created: 20 Jan 2021, 12:09 p.m. | Last Modified: 20 Jan 2021, 12:09 p.m.

Panel Version: 2.52

As described by the Expert Reviewer Lekszas et al 2020 (PMID:32101163) reports a consanguineous Turkish family with 4 sons who presented with a variety of phenotypes including growth retardation, proportionate short stature, clinodactyly of the fifth finger, brachydactyly, platyspondyly of relevance to the skeletal dysplasia panel. A homozygous synonymous substitution in MIA3 was found in all affected family members, with parents being heterozygous. RNA analysis from patient blood samples showed that the variant results in exon eight skipping leading to a truncated protein. Functional studies found this results in reduced collagen expression in U2OS cells.

Created: 20 Jan 2021, noon | Last Modified: 20 Jan 2021, noon

Panel Version: 2.50

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
dentinogenesis imperfecta; short stature; brachydactyly; Platyspondyly; insulin-dependent diabetes mellitus; sensorineural hearing loss; mild intellectual disability

Publications

• 32101163

Red List (low evidence)

The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature

Created: 16 Dec 2020, 2:23 p.m. | Last Modified: 16 Dec 2020, 2:24 p.m.

Panel Version: 2.36

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
short stature; skeletal dysplasia; amelogenesis

Publications

• 32101163