RBM10 – TARP syndrome

TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is a rare X-linked recessive condition caused by deleterious variants in RBM10. Affected males typically present with talipes equinovarus, atrial septal defect, and Robin sequence, often with additional findings such as partial agenesis of the corpus callosum, pulmonary arterial hypertension, and severe intellectual disability (PMID:21910224).

Genetic evidence includes over 35 hemizygous loss-of-function RBM10 variants reported in more than 20 unrelated families, with variants such as c.1352_1353del (p.Glu451ValfsTer66) identified in maternally inherited and de novo contexts (PMID:28577551, PMID:33340101). Multi-family segregation, including maternal mosaicism and recurrence in sibships, confirms X-linked recessive inheritance with at least 2 additional affected relatives carrying the same variant.

Experimental studies have established RBM10 as a critical regulator of alternative splicing. PAR-CLIP and minigene assays demonstrated that RBM10 binds near splice sites to promote exon skipping, and patient-derived cells show aberrant splicing of downstream targets, linking splicing defects to TARP phenotypes (PMID:24000153). Missense variants in the RRM2 domain (e.g., p.Ser315Pro) alter downstream splicing without abolishing nuclear localization, further delineating genotype–phenotype correlations (PMID:37268768).

No conflicting evidence has been reported. The concordance of genetic, segregation, and functional data warrants a Definitive gene–disease classification. RBM10 testing should be included in diagnostic panels for suspected TARP syndrome to enable accurate diagnosis, genetic counseling, and reproductive planning.

Key Take-home: Hemizygous RBM10 loss-of-function variants cause X-linked recessive TARP syndrome through disrupted RNA splicing, and comprehensive genetic and functional evaluation supports definitive association.

References

• American journal of medical genetics. Part A • 2011 • Long-term survival in TARP syndrome and confirmation of RBM10 as the disease-causing gene. PMID:21910224
• EMBO molecular medicine • 2013 • Integrative analysis revealed the molecular mechanism underlying RBM10-mediated splicing regulation. PMID:24000153
• BMC medical genetics • 2017 • Clinical diagnostic exome evaluation for an infant with a lethal disorder: genetic diagnosis of TARP syndrome and expansion of the phenotype in a patient with a newly reported RBM10 alteration. PMID:28577551
• Clinical genetics • 2021 • Phenotypic spectrum of the RBM10-mediated intellectual disability and congenital malformation syndrome beyond classic TARP syndrome features. PMID:33340101

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