Global Developmental Delay, Absent Or Hypoplastic Corpus Callosum, And Dysmorphic Facies

A number sign (#) is used with this entry because of evidence that global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies (GDACCF) is caused by heterozygous mutation in the ZNF148 gene (601897) on chromosome 3q21.

Description

GDACCF is an intellectual disability syndrome apparent soon after birth with neonatal hypotonia, poor feeding, and respiratory insufficiency followed by delayed psychomotor development and intellectual disability with poor speech. Brain imaging shows aplasia or hypoplasia of the corpus callosum. Affected individuals have variable dysmorphic facial features, and some may have dysplastic, cystic kidneys or mild cardiac defects (summary by Stevens et al., 2016).

Clinical Features

Stevens et al. (2016) reported 4 unrelated children with a similar intellectual disability syndrome. The patients presented at birth with respiratory insufficiency, hypotonia, and feeding problems. Three patients had abnormal prenatal imaging findings, including cystic kidneys in 2, one of whom also had a thin corpus callosum, and enlarged cerebral ventricles in the third. The most severely affected patient was a male who died at 6 days of age. He had dysmorphic features and multiple congenital anomalies, including small fontanel, flat occiput, coarse square-shaped face, broad nasal bridge, wide-set eyes with infraorbital creases, retrognathia, upturned nose, prominent columella, long smooth prominent philtrum, narrow palate, widely spaced inverted nipples, and talipes equinovarus. He also had multicystic dysplastic right kidney, left hydronephrosis, and open ductus arteriosus. The 3 other patients, all girls, had delayed psychomotor development with walking around age 3 to 4 years, poor expressive speech, and intellectual disability. All attended special schools, and total IQ of 2 patients was listed as 58 and 59, respectively. Common dysmorphic features included short stature, triangular or oval face, pointed chin, epicanthal folds, wide-set eyes, up- or down-slanting palpebral fissures, smooth or deeply grooved philtrum, prominent columella, wide mouth, and abnormally shaped ears. One patient had very poor growth and severe microcephaly (-8.7 SD), another had documented growth hormone deficiency, and 2 had hyperopia. All had feeding problems, and 1 was still tube-fed at age 6.7 years due to gastrointestinal dysmotility. One of the girls also had a multicystic dysplastic right kidney, coarctation of the aorta, and mitral valve prolapse, but the other 2 girls did not have renal or cardiac anomalies. Brain imaging showed absence of the corpus callosum in 2 patients and hypoplastic corpus callosum in the other 2 patients.

Molecular Genetics

In 4 unrelated children with GDACCF, Stevens et al. (2016) identified 4 different de novo heterozygous truncating mutations in the ZNF148 gene (601897.0001-601897.0004). All mutations occurred in the last exon (exon 9) and were predicted to escape nonsense-mediated mRNA decay and result in expression of a truncated protein. Functional studies of the variants and studies of patient cells were not performed, but Stevens et al. (2016) postulated that a truncated protein could have a dominant-negative or toxic gain-of-function effect. The mutations were found by whole-exome sequencing of a cohort of 2,172 patients with intellectual disability or multiple congenital anomalies. Variants in additional genes were detected in 3 patients, but these could not be related to the phenotype.