Long-term survival in TARP syndrome and confirmation of RBM10 as the disease-causing gene

Abstract

TARP syndrome, comprising Talipes equinovarus, atrial septal defect (ASD), Robin sequence (micrognathia, glossoptosis, and cleft palate), and persistence of the left superior vena cava, is an X-linked condition with pre- or postnatal lethality in affected males. Based on linkage studies and massively parallel sequencing of X-chromosome exons in two families, the disease-causing gene was identified as RBM10. We identified a maternally inherited frameshift mutation in an unrelated patient, confirming RBM10 as the disease gene. This is the first reported individual with TARP syndrome who survived past early infancy, thus expanding the phenotypic spectrum of this disorder. In addition to the characteristic cleft palate, ASD, and persistent superior vena cava, he had low-set and posteriorly angulated ears, upslanting palpebral fissures, cryptorchidism, and structural brain abnormalities including partial agenesis of the corpus callosum, dysplastic enlarged caudate, and cerebellar hypoplasia with megacisterna magna. Preterm delivery, suspected pulmonary hypoplasia, and pulmonary hypertension resulted in chronic lung disease. At the age of 3(7)/(12) years, he remained ventilator-dependent at night, and he was fed exclusively through a gastro-jejunal tube. Sensorineural hearing loss required a hearing aid. Optic atrophy and cortical visual impairment were noted. He was unable to sit independently, was non-communicative and he had severe intellectual disability. Atrial flutter required recurrent ablation of intra-atrial re-entry pathways. The mother's heterozygosity for the RBM10 mutation underscored the importance of accurate diagnosis and counseling for TARP syndrome.

Figure 1

Photographs of the proband at ages 2 2/12 (A, B) and 3 7/12 years (C, D); note the round face, flat supraorbital ridges, upslanting palpebral fissures and mild telecanthus, highly arched eye brows, and low-set and posteriorly angulated ears.

Figure 2

Palms and fingers at age 3 7/12 years, note the absent distal flexion crease in the right fourth finger, mild bilateral brachyclinodactyly of the fifth digit, persistent fetal pads and unusual palmar flexion creases.

Figure 3

Cranial MRI at age 1 year showed a mildly sloping forehead and relatively small frontal lobes (A), markedly short and thin corpus callosum (large square in A), and megacisterna magna (round arrowhead in A). The lower posterior vermis (just above round arrowhead) is borderline small. The caudate nuclei appear large, with the left caudate very large and compressing the frontal horn of the left lateral ventricle (round arrowhead in B, and long arrows labeled “c” in D). Small heterotopias are seen in the subependymal region next to the anterior bodies of the lateral ventricles (all arrows in C, and arrows labeled “het” in D and E). They are adjacent to and difficult to distinguish from the caudate nuclei. The thin corpus callosum, large cavum septum et vergae, and large third ventricle are seen in the midline in B and D-F. The hippocampi are small and dysplastic (long arrow labeled “hip” in D; also seen in E and F). Abbreviations: c, caudate nuclei; het, heterotopia; hip, hippocampus).