A number sign (#) is used with this entry because of evidence that Rabin-Pappas syndrome (RAPAS) is caused by a specific heterozygous missense mutation (R1740W) in the SETD2 gene (612778) on chromosome 3p21.

Rabin-Pappas syndrome (RAPAS) is a multisystemic disorder characterized by severely impaired global development apparent from infancy, feeding difficulties with failure to thrive, small head circumference, and dysmorphic facial features. Affected individuals have impaired intellectual development and hypotonia; they do not achieve walking or meaningful speech. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and possibly endocrine (Rabin et al., 2020).

Rabin et al. (2020) reported 12 unrelated patients (group 1), ranging from 1 month to 12 years of age, with a multisystemic neurodevelopmental disorder associated with a specific de novo heterozygous mutation in the SETD2 gene (R1740W; 612778.0005). The patients were ascertained through collaborative efforts after the mutation was identified, and the phenotype was delineated retrospectively. Nine patients were born prematurely, and 4 mothers of the preterm infants had preeclampsia. All had feeding difficulties and failure to thrive, and most required tube-feeding. None had signs of overgrowth; several had small head circumference or frank microcephaly (down to -4 SD). Respiratory insufficiency, such as hypoventilation, aspiration, or sleep apnea, was commonly observed. The patients had severe global developmental delay with impaired intellectual development, hypotonia, inability to walk independently, and absent language. Seven patients had seizures, many of which were refractory to treatment. Brain imaging showed structural abnormalities in all patients, such as hypoplasia of the corpus callosum, shallow sulci, enlarged ventricles, and pontocerebellar hypoplasia. All patients over 2 months of age developed ophthalmic abnormalities, including telangiectasia of the retina with exudates resembling Coats disease, retinal detachment, optic nerve coloboma, and cataracts. Eight had mixed hearing loss. Common dysmorphic features included hypertelorism, micrognathia, small upturned nose, biparietal narrowing, small forehead, flat face, short palpebral fissures, upslanting palpebral fissures, arched eyebrows, strabismus, wide nasal bridge, broad nasal tip, low hanging columella, maxillary and mandibular hypoplasia, and forward facing ears. Distal skeletal abnormalities of the hands and feet were also observed: these included proximally implanted triphalangeal thumbs and halluces, hypoplastic distal phalanges and nails, and camptodactyly. Other skeletal anomalies included hip dysplasia, contractures, thoracic dysplasia, scoliosis, and craniosynostosis. Almost all had involvement of other organ systems, including genitourinary tract anomalies (cryptorchidism, dysplastic or cystic kidneys) and/or congenital heart defects (mainly septal defects). Eight patients had hyponatremia in infancy.

The heterozygous mutations in the SETD2 gene that were identified in patients with RAPAS by Rabin et al. (2020) occurred de novo.

In 12 unrelated patients (group 1) with RAPAS, Rabin et al. (2020) identified a de novo heterozygous missense mutation in the SETD2 gene (R1740W; 612778.0005). The mutation, which was found through clinical genetics services, was not present in the gnomAD database. The patients were ascertained through collaborative efforts, and the phenotype determined retrospectively. Functional studies of the variant and studies of patient cells were not performed. The patients had a severe phenotype with intellectual disability, inability to walk or speak, and involvement of multiple organ systems, which was considered to be different from that of patients with other SETD2 mutations, including those with a different mutation at the same codon (see R1740Q, 612778.0006).