TBX15 – Pelviscapular Dysplasia

Pelviscapular dysplasia (Cousin syndrome) is an autosomal recessive skeletal disorder characterized by short stature, craniofacial dysmorphism, and hypoplasia of the scapula and pelvis. Four affected individuals from three families (two sibs and two unrelated) have been reported with homozygous loss-of-function TBX15 variants (PMID:24039145).

All cases exhibit homozygous nonsense or frameshift mutations in TBX15, consistent with a loss-of-function mechanism. A representative variant is c.1159C>T (p.Arg387Ter) (PMID:24039145). Recessive inheritance is supported by segregation of homozygosity in the two affected siblings and absence of heterozygous carriers in unaffected relatives.

The variant spectrum to date comprises solely truncating alleles predicted to abolish TBX15 transcriptional activity. No missense or regulatory variants have been implicated, underscoring a critical dosage requirement for TBX15 in skeletal development.

Functional assessment in Tbx15–/– mice reveals significantly shortened body and limb length, reduced weight, droopy ear positioning, and facial shortening, mirroring key human phenotypes (PMID:34938962). These findings confirm that TBX15 deficiency perturbs skeletal morphogenesis.

Integration of genetic and experimental data supports a moderate ClinGen classification: multiple unrelated probands with homozygous loss-of-function alleles, segregation in one family, and concordant mouse model phenotypes. TBX15 genetic testing should be considered in patients with short stature, short neck, and scapular/pelvic hypoplasia.

Key Take-home: Homozygous truncating variants in TBX15 cause autosomal recessive pelviscapular dysplasia; clinical testing enables definitive diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2013 • Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome. PMID:24039145
• FASEB bioAdvances • 2021 • The effects of Tbx15 and Pax1 on facial and other physical morphology in mice. PMID:34938962

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