A number sign (#) is used with this entry because of evidence that Radio-Tartaglia syndrome (RATARS) is caused by heterozygous mutation in the SPEN gene (613484) on chromosome 1p36.

Radio-Tartaglia syndrome (RATARS) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, speech delay, and variable behavioral abnormalities. Affected individuals show hypotonia, mild motor difficulties, and craniofacial dysmorphism. Brain imaging may show nonspecific defects; rare patients have seizures or pyramidal signs. A subset of individuals may have congenital heart defects, precocious puberty, and obesity in females. Some of the features are similar to those observed in patients with chromosome 1p36 deletion syndrome (607872) (summary by Radio et al., 2021).

Radio et al. (2021) reported 34 individuals from 33 unrelated families with a similar neurodevelopmental disorder ascertained through genetic analysis. The patients had global developmental delay with impaired intellectual development, and poor speech. Behavioral or psychiatric abnormalities, including autistic features, anxiety, aggressive behavior, and ADHD, were noted in 81%; 1 patient (S20) developed schizophrenia. Some patients were able to attend special schools. Other common features included generalized hypotonia (73%), oromotor hypotonia (43%), gait imbalance (52%), and pyramidal signs (25%). Three patients had seizures. Brain imaging showed abnormalities in 14 (64%) of 22 patients studied. Features included polymicrogyria, heterotopia, cerebellar atrophy, periventricular white matter defects, agenesis of the corpus callosum, and tethered cord. There was a characteristic facial appearance with rare microcephaly, broad forehead (26%), frontal bossing (16%), bitemporal narrowing (39%), arched elongated eyebrows (39%), synophrys (33%), telecanthus (26%), epicanthal folds (39%), dysplastic ears (35%), and broad nose with bulbous/prominent nasal tip (52%). Some patients had long philtrum, thin upper lip, tooth abnormalities, high-arched palate, or pointed chin. Extraneurologic features were also present, including congenital heart defects (28%) such as ventricular septal defects, patent foramen ovale, patent ductus arteriosus, and mitral regurgitation, as well as scoliosis, brachydactyly, toe anomalies, dry skin, and hemangiomas. Precocious puberty was found in a subset of subjects (22%), and affected females tended to have increased BMI or to be obese.

The heterozygous mutations in the SPEN gene that were identified in most of the patients with RATARS by Radio et al. (2021) occurred de novo. In 2 families, the transmission pattern was consistent with autosomal dominant inheritance.

In 34 patients, including 2 sibs, with RATARS, Radio et al. (2021) identified heterozygous truncating mutations in the SPEN gene (613484.0001-613484.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The patients were ascertained through the GeneMatcher program and the DECIPHER database. The vast majority of the mutations occurred de novo, although they were inherited from an affected parent in 2 families. The mutations were distributed throughout the coding region of the gene, and there were no obvious genotype/phenotype correlations. In vitro functional expression studies of the variants were not performed, but they were predicted to result in a loss of function with haploinsufficiency. Genomewide methylation profiling did not show a substantial difference between the pattern of cells derived from 11 of the patients compared to controls. However, when restricted to females with SPEN truncating mutations, there was a distinct difference in the X-chromosome epigenetic signature compared to controls, suggesting a role for SPEN in X-chromosome inactivation and X-linked gene silencing. The report defined a paradigm of an X chromosome-specific episignature that underlies specific syndromic traits and could be used to classify individuals with neurodevelopmental disorders.