Mental Retardation, Autosomal Dominant 32

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-32 (MRD32) is caused by heterozygous mutation in the KAT6A gene (601408) on chromosome 8p11.

Clinical Features

Arboleda et al. (2015) reported 4 unrelated children, ranging from 2 years, 11 months to 5 years of age, with a similar constellation of developmental abnormalities. Common features included microcephaly (-2.1 to -3.0 SD), poor overall growth, and delayed psychomotor development with intellectual disability and absent speech. Three patients were hypotonic and 2 were dystonic. Dysmorphic facial features were somewhat variable but included prominent nasal bridge or root, dental anomalies, strabismus, and epicanthal folds. One patient had a cleft palate and another had optic nerve atrophy. Two patients had an atrial septal defect, and a third had a ventricular septal defect. Two patients had chronic lung disease, 3 had gastrointestinal reflux and feeding difficulties, and 1 had intestinal malrotation.

Tham et al. (2015) reported 6 children 10 years of age or younger, including a set of monozygotic twins, from 5 unrelated families with intellectual disability and distinct syndromic features. All patients were delivered by emergency cesarean section and 4 had severe neonatal respiratory distress. All had neonatal hypotonia, some with stiff extremities, and delayed psychomotor development with lack of speech. Dysmorphic facial features were subtle and somewhat variable, including craniosynostosis, microcephaly, bitemporal narrowing, microretrognathia, strabismus, ptosis, broad nasal tip, low-set or posteriorly rotated ears, thin upper lip, and downturned corners of the mouth. Additional features included congenital heart defects, including septal defects and patent ductus arteriosus, and feeding difficulties. Brain imaging was essentially normal, except for nonspecific changes in 3 patients. Two patients had mild and controlled seizures and 2 had cortical visual impairment.

Millan et al. (2016) reported 6 unrelated individuals with a common phenotype consisting of a neurodevelopmental disorder with severe speech delay, hypotonia, and facial dysmorphism. Patient 1 was a 2-year-old female who presented in the neonatal period with an atrial septal defect and mild mitral prolapse requiring surgical correction. She was found to be microcephalic a few months after birth, and was nonambulatory and nonverbal at 27 months. Patient 2 was a 9-year-old male who had microcephaly and was nonverbal but communicated well through sign language. He also had mitral valve prolapse with regurgitation. Patient 3 was an 11-year-old girl with microcephaly who walked at 24 months and said her first words at age 6 years. Patient 4 was a 5-year-old girl who had a patent foramen ovale and patent ductus arteriosus. Her head size was normal. She had been nonverbal at age 3 years but by age 5 she had 3 words and approximately 50 signs. Patient 5 was a 6-year-old female who had developed stereotypical behaviors and had 3 words at age 3 years. She sat at 5 months and walked at 19 months. Patient 6 was a 29-year-old man with autism spectrum disorder and obsessive-compulsive behaviors and who was nonverbal. He developed complex partial seizures with secondary generalization at age 9 years. He had been seizure-free on antiepileptic medication for 2 years prior to the report. Brain MRI showed absence of an olfactory bulb. Facial dysmorphisms, present in all, were varied but frequently included broad or bulbous nose or nasal tip, downslanting palpebral fissures or ptosis, and abnormal ears. Most had a history of feeding difficulties including gastroesophageal reflux resulting in failure to thrive.

Molecular Genetics

In 4 unrelated children with MRD32, Arboleda et al. (2015) identified 2 different de novo heterozygous truncating mutations in the KAT6A gene (601408.0001 and 601408.0002). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Three patients had been ascertained from a cohort of 298 individuals with developmental delay who underwent exome sequencing, thus representing about 1% (3 of 298) of patients. Studies of patient cells showed alterations in acetylation of histone 3 lysine-9 (H3K9) and H3K18 (see HIST1H3A, 602810), as well as changes in signaling downstream of p53 (TP53; 191170), suggesting disruption of multiple pathways involved in apoptosis, metabolism, and transcriptional regulation.

In 6 patients, including a set of monozygotic twins, from 5 unrelated families with MRD32, Tham et al. (2015) identified 5 different de novo heterozygous truncating mutations in the KAT6A gene (see, e.g., 601408.0003-601408.0005). All the mutations were predicted to result in truncation of the protein within the C-terminal acidic domain, leaving the HAT domain intact. No patient cells were available for studies, and functional studies of the variant were not performed.

Using trio whole-exome sequencing (WES) in 6 patients with a neurodevelopmental disorder with severe speech delay, hypotonia, and facial dysmorphism, Millan et al. (2016) identified 6 de novo mutations in the KAT6A gene. All but 1 were frameshift or nonsense mutations. One patient (patient 4) had an independent occurrence of the R1024X variant (601408.0002) previously described by Arboleda et al. (2015).