Helsmoortel-Van Der Aa Syndrome

A number sign (#) is used with this entry because of evidence that Helsmoortel-Van der Aa syndrome (HVDAS) is caused by heterozygous mutation in the ADNP gene (611386) on chromosome 20q13.

Clinical Features

Helsmoortel et al. (2014) reported 10 unrelated children with intellectual disability, autism spectrum disorder, and dysmorphic facial features. The patients were ascertained from several large cohorts of individuals with similar features. Nine of the 10 patients had developmental delay apparent in infancy, and 5 of the patients had severe intellectual disability in childhood, with some being nonverbal. Neuropsychiatric features were relatively common, including attention deficit/hyperactivity disorder, anxiety disorder, obsessive compulsive behavior, and stereotypic behaviors. Other frequent findings included hypotonia, feeding problems in infancy, recurrent infections, short stature, joint laxity, and hand abnormalities. Two patients had seizures and 3 had a congenital heart defect. Dysmorphic features varied, but included prominent forehead, high hairline, downslanting palpebral fissures, notched eyelids, broad nasal bridge, thin upper lip, and smooth philtrum.

Pescosolido et al. (2014) reported a 6-year-old girl with HVDAS who presented in infancy with hypotonia, multiple cyanotic episodes thought to be due to breath holding, and feeding difficulties. She showed global developmental delay with delayed language, attention deficit-hyperactivity disorder, a nonspecific mood disorder, and autistic features. Dysmorphic features included broad forehead and slightly tented lips. She also had visual problems, including hypermetropia, cortical visual impairment, exotropia, mild amblyopia, and astigmatism. Treatment resulted in significant improvement in her visual function.

The Deciphering Developmental Disorders Study (2015) identified 4 patients with de novo mutations in the ADNP gene that caused intellectual disability. One patient also had juvenile cataract, microcephaly, muscular hypotonia of the trunk, inverted nipples, sparse scalp hair, long palpebral fissures, abnormality of fingertips, and joint laxity. A second patient had microcephaly, iris coloboma, joint hypermobility, hirsutism, long palpebral fissures, depressed nasal bridge, thick lower lip vermilion, widely spaced teeth, and smooth philtrum. A third patient had plagiocephaly, obesity, and inguinal hernia, and the fourth patient had generalized neonatal hypotonia, bilateral ptosis, gastroesophageal reflux, cryptorchidism, plagiocephaly, low-set ears, first-degree microtia, broad thumb, and respiratory distress.

Molecular Genetics

In 10 unrelated patients with Helsmoortel-Van der Aa syndrome, Helsmoortel et al. (2014) identified 9 different de novo heterozygous truncating mutations in the ADNP gene (see, e.g., 611386.0001-611386.0005). The initial mutations were found by whole-exome sequencing, whereas additional mutations were found by direct analysis of the ADNP gene. The patients with MRD28 were ascertained from several cohorts totaling 5,776 unrelated patients with intellectual disability and/or autism spectrum, thus accounting for 0.17% of these patients. All of the mutations occurred at the 3-prime end of the last exon of the ADNP gene and were predicted to result in the loss of at least the last 166 C-terminal residues, with escape from nonsense-mediated mRNA decay. Available cells from 4 patients showed significantly increased levels of mutant mRNA compared to wildtype, suggesting deregulation of a negative expression feedback loop. Helsmoortel et al. (2014) noted that mutations in other SWI/SNF components of the BAF complex, such as SMARCB1 (601607) and ARID1B (614556), have been identified in patients with intellectual disability, and hypothesized that the ADNP mutations cause a dominant-negative effect on the recruitment of the BAF complex, resulting in deregulation of gene expression and a disruption of neuronal processes.

In a 6-year-old girl with HVDAS, Pescosolido et al. (2014) identified a de novo heterozygous truncating mutation in the ADNP gene (Y719X; 611386.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, had previously been reported by Helsmoortel et al. (2014), suggesting that it is a recurrent mutation. Functional studies of the variant were not performed.

The Deciphering Developmental Disorders Study (2015) examined 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements. The ADNP gene was implicated in a gene-specific analysis (p = 4.59 x 10(-11)). In 4 patients with intellectual disability and other features, the Deciphering Developmental Disorders Study (2015) detected 3 de novo heterozygous mutations in the ADNP gene. All 3 of the mutations resulted in frameshift. No functional studies were performed.