TENT5A – Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder marked by bone fragility, congenital bowing of long bones, blue sclerae, respiratory distress, fever and recurrent fractures. Biallelic variants in TENT5A (formerly FAM46A) have been implicated in autosomal recessive OI with early-onset and severe skeletal manifestations. The inheritance pattern is consistent with autosomal recessive transmission and has been confirmed in consanguineous families and sib pairs.

Initial exome sequencing of a patient with Stüve-Wiedemann–like features revealed a homozygous frameshift mutation c.612_613dup (p.Ser205TyrfsTer13) leading to osteogenesis imperfecta manifestations (PMID:29358272). Screening of 25 additional OI cases without known mutations identified a homozygous missense variant c.380A>G (p.His127Arg) in two affected siblings and another homozygous missense change c.692A>G (p.Asp231Gly) in a separate patient (PMID:29358272).

The variant spectrum in TENT5A comprises at least one truncating allele and two missense alleles, all observed in the homozygous state in affected individuals. These variants segregate with disease in a sib pair from consanguineous parents (2 affected relatives) and in additional unrelated probands, supporting a consistent autosomal recessive inheritance (PMID:29358272).

In a cohort of 140 Turkish OI families, biallelic variants in TENT5A constituted part of the autosomal recessive OI spectrum, with 18 biallelic variants reported across nine genes including FAM46A (PMID:34902613). This underscores the contribution of TENT5A to recessive OI subtypes in diverse populations.

Functional studies demonstrate specific expression of TENT5A in human osteoblasts and identify an ENU-derived mouse model harboring a nonsense Fam46a mutation that recapitulates reduced cortical thickness, limb deformities and diminished body size, mirroring the human phenotype (PMID:29358272). These data support a loss-of-function mechanism leading to defective bone matrix deposition.

Collectively, the genetic and experimental evidence supports a Moderate ClinGen-level association between TENT5A and autosomal recessive OI. Screening of TENT5A should be considered in patients with unexplained recessive OI, particularly in consanguineous contexts.

References

• Journal of medical genetics • 2018 • FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. PMID:29358272
• Bone • 2022 • Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants. PMID:34902613

Evidence Based Scoring (AI generated)