Tarp Syndrome

A number sign (#) is used with this entry because of evidence that TARP syndrome is caused by hemizygous mutation in the RBM10 gene (300080) on chromosome Xp11.

Clinical Features

Gorlin et al. (1970) described a kindred in which multiple males, related through normal females, had Pierre Robin syndrome with congenital heart malformation and clubfoot. Other possible reports of the syndrome were noted; e.g., Sachtleben (1964) reported 2 brothers with cleft palate, congenital heart disease, and clubfoot. In a brief follow-up note, Gorlin et al. (1971) stated that subsequent to the time of their report 'two more affected sons have been born to sisters of our proband's mother.'

Kurpinski et al. (2003) studied a 4-generation family with a lethal disorder with features including talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava. All affected males died in infancy. A portion of this pedigree included individuals originally studied by Gorlin et al. (1970). Kurpinski et al. (2003) designated this disorder TARP syndrome.

Johnston et al. (2010) reported 3 male cousins with Robin sequence, talipes equinovarus, and cardiac defects. One boy, who lived only 5 minutes, had a large atrial septal defect and marked underdevelopment of pulmonary alveoli on postmortem examination. The second boy, who died at 8 days of life with liver failure, kidney failure, hyaline membrane disease, athetoid movements, and seizures, also had basal ganglia hemorrhage and subdural hematoma on head ultrasound; autopsy was declined. Few clinical details were available for the third boy, who died of his multiple congenital anomalies.

Johnston et al. (2014) reported 5 boys from 3 families with mutation in the RBM10 gene and more variable features of TARP syndrome. None had talipes, and one also lacked Robin sequence and atrial septal defect. One boy had unilateral postaxial toe polydactyly, absent septum pellucidum, small cerebellar vermis, and horseshoe kidney; his brother had bilateral 2-3 toe syndactyly, small cerebellar vermis, and horseshoe kidney. The boys died at ages 2.5 months and 4 months from respiratory failure. A third pregnancy in this family was terminated because of the finding of similar features. The fourth boy presented at birth with tetralogy of Fallot, incomplete formation of inferior vermis and cerebellum, and optic nerve hypoplasia. The fifth boy had a short sternum and dysplastic proximal radii, cerebellar hemorrhage, tortuous duodenum, and abnormal hair pattern. He died at 14 months of age from respiratory failure.

Inheritance

The transmission pattern of TARP syndrome in the 4-generation family studied by Kurpinski et al. (2003) was consistent with X-linked recessive inheritance.

Mapping

Kurpinski et al. (2003) performed an X-chromosome linkage scan using 14 unaffected members of the family with TARP syndrome originally described by Gorlin et al. (1970) and 40 short tandem repeat (STR) markers. They found that the gene mapped to an 11-cM region in Xp11.23-q13.3. Markers DXS1003 and DXS8092 flanked the region and 3-point linkage analyses revealed a maximum lod score of 2.75 at marker DXS1039. The locus was mapped without genotyping any affected individuals and demonstrated that rare, lethal disorders can be evaluated by genetic linkage, even when no affected individuals are available for study.

Johnston et al. (2010) performed haplotype analysis in a family with TARP syndrome with the 3 markers previously used by Kurpinski et al. (2003) as well as additional markers on chromosome Xp11.23-q13.3, and found that haplotypes were consistent with affected or carrier status in all individuals tested. Johnston et al. (2010) noted that a linked STR haplotype in the 2 families was distinct, suggesting that mutations in the 2 families were likely to be distinct.

Molecular Genetics

Using massively parallel sequencing of X chromosome exons and screening of sequence data with successive filtering criteria, Johnston et al. (2010) identified a frameshift and a nonsense mutation in the RBM10 gene (300080.0001 and 300080.0002, respectively) in affected individuals and obligate carriers from 2 families with TARP syndrome, 1 of which was originally described by Gorlin et al. (1970). Johnston et al. (2010) demonstrated that RBM10 is expressed in midgestation mouse embryos in the branchial arches and limbs, consistent with the human phenotype.

By whole-exome sequencing in a male proband with TARP syndrome who had an initial tentative diagnosis of atypical orofaciodigital syndrome, Johnston et al. (2014) identified a nonsense mutation (Q150X; 300080.0003) in the RBM10 gene. X-chromosome inactivation studies showed absence of skewing in maternal DNA. Sanger sequencing and restriction enzyme digestion confirmed the presence of the mutation in the proband and identified low-level mosaicism in the mother. Two of his brothers had similar clinical features, but DNA samples were not available.