A number sign (#) is used with this entry because of evidence that congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) is caused by heterozygous mutation in the ATN1 gene (607462) on chromosome 12p13.

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) is a syndromic neurodevelopmental disorder characterized by severe global developmental delay, impaired intellectual development with poor or absent language, significant motor disability with inability to walk, dysmorphic facial features, skeletal anomalies, and variable congenital anomalies. Most patients also have seizures and structural brain abnormalities (summary by Palmer et al., 2019).

Palmer et al. (2019) reported 8 unrelated patients, ranging in age from 2 months to 9 years, with a similar neurodevelopmental disorder. One of the patients (patient 8), who died at 2 months of age, had previously been reported by Mosca et al. (2007) as having a multiple congenital anomaly syndrome with dysmorphic facial features, cleft palate, axial hypotonia, peripheral hypertonia, polymicrogyria, and cerebellar vermis hypoplasia. The patients reported by Palmer et al. (2019) presented soon after birth with hypotonia, severe to profound global developmental delay, absent language, and severe motor delay, with variable inability to roll, sit, or walk independently. Six patients had cortical visual impairment, and 5 had hearing impairment. Several other patients had recurrent otitis media. Five patients had overt seizures, including 4 with severe infantile seizures consistent with epileptic encephalopathy. Most patients, even those without seizures, had EEG abnormalities, such as background slowing and epileptiform discharges. Neurologic status included central hypotonia, often with peripheral hypertonia or spasticity. Common dysmorphic features included tall forehead with bitemporal narrowing, long philtrum, retrognathism, low-set and posteriorly rotated ears, sparse lateral forehead hair, deep-set eyes with abnormal palpebral fissures, bulbous nasal tip, open mouth with thin upper lip, and hand and foot anomalies, including overlapping toes, camptodactyly, persistent fetal fingertip pads, and abnormalities of the palmar creases. Other skeletal anomalies included joint hypermobility, craniocervical stenosis, scoliosis, and hip dysplasia. Congenital structural anomalies were common, but somewhat variable between individuals: 4 had cardiac malformations, including atrial and ventricular septal defects and/or abnormalities of the aorta and superior vena cava, 2 had cleft palate, 3 had renal anomalies, and 2 had anteriorly placed anus. Feeding problems, including gastroesophageal reflux and constipation were common; several patients required tube feeding. More variable features included obstructive sleep apnea, cryptorchidism, and inverted nipples. Six patients had abnormal brain imaging, including cerebral atrophy, thin corpus callosum, absence of the falx cerebri, cerebellar vermis hypoplasia, and polymicrogyria.

The heterozygous mutations in the ATN1 gene that were identified in patients with CHEDDA by Palmer et al. (2019) occurred de novo.

In 8 unrelated children with CHEDDA, Palmer et al. (2019) identified 8 different de novo heterozygous mutations in exon 7 of the ATN1 gene (see, e.g., 607462.0002-607462.0006), all resulting in substitutions within the highly conserved 16-amino acid histidine-rich 'HX repeat' motif near the C terminus. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. This HX repeat is distal to the expanded repeat responsible for dentatorubral-pallidoluysian atrophy (DRPLA; 125370). Nuclear magnetic resonance analysis of a synthesized peptide containing 1 of the mutations (H1060Y; 607462.0005) showed that the mutation resulted in a perturbation of the structural and functional integrity of the HX repeat, and altered zinc-binding properties. Additional functional studies of the variants and studies of patient cells were not performed. However, Palmer et al. (2019) noted that de novo disruptions of a similar HX repeat motif in the RERE gene (605226) and the AUTS2 gene (607270) have been noted in patients with neurocognitive phenotypes. ATN1 also lies within the critical region for Pallister-Killian syndrome (PKS; 601803), which has an overlapping phenotype. Despite the absence of these variants in gnomAD, all could be classified as 'variants of uncertain significance' according to ACMG guidelines.