A number sign (#) is used with this entry because of evidence that Chopra-Amiel-Gordon syndrome (CAGS) is caused by heterozygous mutation in the ANKRD17 gene (615929) on chromosome 4q13.

Chopra-Amiel-Gordon syndrome (CAGS) is an autosomal dominant disorder characterized by developmental delay and/or impaired intellectual development, speech delay, facial dysmorphism, and variable other features, including recurrent bacterial infections, ophthalmologic abnormalities, and nonspecific brain abnormalities (Chopra et al., 2021).

Chopra et al. (2021) reported clinical features of 34 patients from 32 families ascertained using GeneMatcher and DECIPHER. The patients ranged in age from 4 months to 34 years. The primary features in 31 patients were global developmental delay and/or impaired intellectual development. The severity was variable, with 19 patients in the moderate to severe range and 12 in the mild or borderline range. Speech development was delayed in 29 individuals, including 6 with absent speech. Less commonly reported developmental features included autism spectrum disorder and attention deficit-hyperactivity disorder (ADHD). Postnatal microcephaly was reported in 7 patients, and macrocephaly in 4. Epilepsy was reported in 9 patients. Neuroimaging, performed in 23 individuals, identified abnormalities in 11 patients; abnormalities included decreased white matter volume in 3 patients, thinning of the corpus callosum in 2, optic nerve hypoplasia in 2, localized hyperintensity in 2, right temporal sclerosis in 1, dilated Virchow-Robin spaces in 1, and periventricular nodular heterotopia in 1. Ophthalmologic abnormalities were reported in 13 of 23 individuals. Nine patients had recurrent bacterial infections, 1 patient had recurrent viral infections, and another patient had recurrent viral and bacterial infections. A pair of monozygotic twins with discordant phenotypes were included in the patient cohort. In the 24 patients for whom photographs were available, dysmorphic features included a triangular-shaped face in 10; a high anterior hairline in 19; deep-set eyes in 5, almond-shaped eyes in 8; periorbital fullness in 6, thick nasal alae and flared nostrils in 9, full cheeks in 7, and a thin upper lip in 12. The degree of dysmorphism was variable.

The heterozygous mutations in 29 of the 34 patients with CAGS reported by Chopra et al. (2021) occurred de novo. One patient inherited the disorder from an affected parent, and another patient inherited it from a parent with low-level mosaicism for an ANKRD17 mutation. Parental inheritance was not determined in 3 patients.

In a patient (individual 6) with Chopra-Amiel-Gordon syndrome, Chopra et al. (2021) identified a de novo heterozygous 1.16-Mb deletion encompassing 7 genes, including ANKRD17, by array CGH. The other 6 genes in the region were associated with an autosomal recessive pattern of disease inheritance when mutated (ADAMTS3, 605011; ALB, 103600; AFP, 104150) or were not known to be associated with a disease (COX18, 610428; AFM, 104150; RASSF6, 612620). Chopra et al. (2021) therefore considered ANKRD17 to be the most likely candidate gene underlying the patient's phenotype. Functional studies were not performed.

In 34 patients from 32 families with Chopra-Amiel-Gordon syndrome, Chopra et al. (2021) identified heterozygous mutations in the ANKRD17 gene (see, e.g., 615929.0001-615929.0005). The mutations included 21 truncating or canonical splice site mutations, 9 missense mutations, 1 in-frame indel, and 1 microdeletion including ANKRD17 and 6 other genes. Molecular modeling suggested that most of the missense mutations disrupted the stability of ankyrin repeats.