A number sign (#) is used with this entry because of evidence that agenesis of corpus callosum, cardiac, ocular, and genital syndrome (ACOGS) is caused by heterozygous mutation in the CDH2 gene (114020) on chromosome 18q12.

Agenesis of corpus callosum, cardiac, ocular, and genital syndrome (ACOGS) is a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, craniofacial dysmorphisms, and ocular, cardiac, and genital anomalies (Accogli et al., 2019).

Accogli et al. (2019) reported 9 individuals with mutations in the CDH2 gene, who exhibited a strikingly similar clinical and radiologic phenotype, including developmental delay/intellectual disability, callosal malformations, cardiac and ocular abnormalities, and characteristic facial dysmorphisms. One patient (patient 2) had been previously studied by Uccella et al. (2019). All patients exhibited developmental delay, and half had mild to moderate intellectual impairment. Two individuals met diagnostic criteria for autism spectrum disorder, 1 displayed self-injurious behaviors, and another had several neuropsychiatric issues, including auditory hallucinations. Seven of 9 patients had agenesis of the corpus callosum, and 1 had corpus callosum hypoplasia; brain imaging was not reported for the remaining patient. Hypothalamic adhesion was identified in 5 patients, periventricular nodular heterotopia in 4, and 2 individuals had an interhemispheric cyst communicating with the third ventricle. Four patients had hypoplastic or dysplastic tentorium, 2 patients had megacisterna magna, and another showed an atretic parietal cephalocele. A wide range of congenital cardiac defects were present, including defects of the atrioventricular canal in 2 patients, aortic coarctation in 2, dextrocardia with right pulmonary artery hypoplasia in 1, and tricuspid regurgitation in 1. Two individuals developed seizures, which were focal in 1 and infantile spasms in the other. Half of the cohort exhibited congenital eye defects, including Peters anomaly in 2 patients, unilateral ptosis with Duane anomaly in 1, congenital cataracts in 1, and strabismus in 3 patients, all requiring surgical intervention. Hyposmia was reported in 3 patients, 1 of whom also had hypogeusia. One patient exhibited congenital mirror movements. Shoulder deformities were present in 3 patients, with 2 showing Sprenger deformity and 1 having absence of shoulder muscles. Four of 5 male patients had genital anomalies, including cryptorchidism in 3 and micropenis in 1. Four patients had macrocephaly, and 1 had relative macrocephaly at last evaluation. Craniofacial dysmorphisms observed included broad and prominent forehead, downslanting palpebral fissures, deep-set eyes, low-set posteriorly rotated ears with thick helices and earlobes, thin upper lip, and pointed chin.

Reis et al. (2020) described 4 children with agenesis of the corpus callosum, Peters anomaly, dysmorphic features, and developmental delays, who had mutations in the CDH2 gene. One of the patients (patient 2) had previously been studied as patient 6 by Reis et al. (2008). Dysmorphic features in these children included hypertelorism, flat nasal bridge, low-set or posteriorly rotated ears, upturned earlobes, thin upper lip, small mouth with downturned corners, and low anterior hairline. Neurologic features included cognitive delays and mild hypotonia with hypertonic extremities; additional brain malformations included hypoplasia of the cerebellar vermis, incomplete hippocampal rotation, and absent septum pellucidum. One patient (patient 4) was reported to have Peters anomaly and umbilical hernia, but no other syndromic features were noted at age 18 months; also, an older brother was reported to have Peters anomaly, but the family was lost to follow-up.

The heterozygous mutations in the CDH2 gene that were identified in patients with ACOGS by Accogli et al. (2019) occurred de novo.

The transmission pattern in 1 family reported by Reis et al. (2020) was consistent with autosomal dominant inheritance; in 1 patient the mutation was shown to have occurred de novo; and in the remaining 2, inheritance could not be established.

In a 9-year-old boy (patient 2) with agenesis of the corpus callosum, mild intellectual disability and autism spectrum disorder, Duane anomaly, craniofacial dysmorphisms, tricuspid regurgitation, and cryptorchidism, previously reported by Uccella et al. (2019), Accogli et al. (2019) identified heterozygosity for a de novo missense mutation in the CDH2 gene (D597N; 114020.0003). From the GeneMatcher database, the authors ascertained 8 additional cases with overlapping phenotypes and heterozygous de novo mutations in the CDH2 gene (see, e.g., 114020.0004-114020.0007). Noting the neurodevelopmental features observed in the affected individuals, including agenesis of the corpus callosum, periventricular nodular heterotopias, hyposmia, mirror movements, and Duane anomaly, the authors suggested that CDH2 plays a critical role in neuronal migration and axon pathfinding.

In a male patient (patient 1) with agenesis of the corpus callosum, Peters anomaly, dysmorphic features, and cognitive delay, Reis et al. (2020) performed trio analysis of exome data and identified heterozygosity for a de novo splicing variant in the CDH2 gene (114020.0008). Review of exome data from 145 additional probands with developmental ocular anomalies identified 3 more patients with Peters anomaly, agenesis of the corpus callosum, and other syndromic features who had heterozygous missense mutations in the CDH2 gene, including a boy (patient 2) who previously had been studied as patient 6 by Reis et al. (2008) (V162D; 114020.0009). In 1 patient (patient 4), a P603S mutation was inherited from an apparently unaffected mother who had not undergone formal eye exam; however, the family was lost to follow-up.