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This summary describes the association between BMPER (HGNC:24154) and diaphanospondylodysostosis, a severe skeletal dysplasia (MONDO_0011946). Multiple independent case reports and multi‐patient studies have consistently documented a spectrum of clinical manifestations including vertebral ossification defects, short neck, protuberant abdomen, respiratory complications, and renal anomalies (PMID:22581610, PMID:28815954). The disorder is inherited in an autosomal recessive manner and is characterized by both lethal and attenuated forms, emphasizing the heterogeneity in presentation and clinical outcomes.
Genetic evidence supporting this association is robust. Multiple variant types in BMPER, including missense, loss‑of‑function, and splice variants, have been reported across several unrelated probands. For example, one study identified the coding variant c.322T>C (p.Cys108Arg) in a patient with classical features of diaphanospondylodysostosis (PMID:28815954). Moreover, several reports have documented familial segregation of deleterious variants in BMPER with affected siblings and other relatives, further strengthening the genotype‑phenotype correlation (PMID:26467725).
Segregation data from these studies reveal that in some families, multiple affected relatives share biallelic BMPER mutations, which underscores the importance of considering family history in diagnostic evaluations. The collective genetic evidence across more than 10 probands from independent studies demonstrates a consistent pattern of recessively inherited disruption in BMPER function.
Functional studies complement the genetic findings by elucidating the role of BMPER in BMP signaling and skeletal morphogenesis. Experiments in mouse models and cellular assays have shown that loss or alteration of BMPER leads to reduced ossification and defective cartilage differentiation, which is in line with the clinical features observed in patients (PMID:17035289). These data provide mechanistic support that BMPER dysfunction is pathogenic and contributes to the DSD phenotype.
Integration of the genetic and experimental data results in a strong overall association between BMPER and diaphanospondylodysostosis. The data not only aid in establishing a molecular diagnosis but also support clinical decision‐making by informing prognosis and guiding therapeutic interventions. Importantly, the cumulative evidence exceeds the ClinGen scoring maximum, underscoring its utility in both clinical diagnostics and future research.
Key Take‑home sentence: BMPER mutations, inherited in an autosomal recessive fashion, are strongly associated with diaphanospondylodysostosis, with converging genetic and functional evidence that enables precise diagnostic and therapeutic strategies.
Gene–Disease AssociationStrongMultiple unrelated probands (>10 in aggregate across several independent studies [PMID:22581610], [PMID:28815954], [PMID:34288564]), clear autosomal recessive segregation, and consistent clinical features confirm a strong gene-disease association. Genetic EvidenceStrongDiverse variant types—including missense, loss-of-function, and splice variants such as c.322T>C (p.Cys108Arg)—have been identified in several independent cases, with familial segregation observed in multiple studies ([PMID:26467725], [PMID:34877902]). Functional EvidenceModerateFunctional assays and animal models demonstrate that BMPER modulates BMP signaling critical for skeletal development, with loss-of-function studies reproducing key aspects of the phenotype ([PMID:17035289]). |