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.

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental disorder characterized by impaired intellectual development/motor delay, autism spectrum disorder, facial dysmorphisms, hypotonia, congenital heart disease, visual difficulties, and gastrointestinal issues (summary by Breen et al., 2020).

Helsmoortel et al. (2014) reported 10 unrelated children with impaired intellectual development, 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 (ADHD), 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 impaired intellectual development. 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.

Van Dijck et al. (2019) described the clinical features of a worldwide cohort of 78 patients, some of whom were previously reported, with HVDAS. The average age of the patients was 8 years and 2 months (range, 1-40 years). Seventy-three of 73 individuals had impaired intellectual development, which was mild in 9, moderate in 26, and severe in 38. Motor delay was reported in 71 patients, and speech delay was reported in 70 patients, with 14 having no speech. Feeding and gastrointestinal issues were reported in 60 of 72 patients, with gastroesophageal reflux as the most common issue, being reported in 38 patients. Hypotonia was reported in 54 patients, seizures were reported in 12 patients, and behavioral problems were reported in 48 patients. Brain imaging abnormalities were reported in some patients and included wide ventricles (15 patients), cerebral atrophy (8 patients), underdevelopment of the corpus callosum (9 patients), delayed myelination (4 patients), white matter lesions (4 patients), and cortical dysplasia (2 patients). Other systemic involvement included structural cardiac abnormalities (26 patients), urogenital abnormalities (21 patients), joint hypermobility (23 patients), and hand or foot abnormalities (43 patients).

Van Dijck et al. (2019) identified heterozygous mutations in the ADNP gene in a worldwide cohort of 78 individuals with HVDAS, some of whom had previously been reported. Sixty-eight mutations were confirmed to be de novo, 8 mutations were of unknown inheritance, and 2 C-terminal mutations were inherited.

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.

Van Dijck et al. (2019) reported mutations in the ADNP gene in a worldwide cohort of 78 individuals with HVDAS, some of whom had previously been reported. There were no reports of consanguinity or affected sibs. Forty-six unique mutations were identified, of which 25 were nonsense and 21 were frameshift. Forty-three of the mutations were located in the last exon. Some mutations indicated mutation hotspots (see, e.g., 611386.0005 and 611386.0009).

Bend et al. (2019) performed genomewide DNA methylation analysis on peripheral blood DNA from 22 patients with HVDAS and identified 2 distinct episignatures caused by mutation in the ADNP gene. The first episignature (epi-ADNP-1) included approximately 6,000 mostly hypomethylated CpGs, and the second (epi-ADNP-2) included approximately 1,000 predominantly hypermethylated CpGs. The episignatures correlated with the location of the mutations, with epi-ADNP-1 mutations located outside nucleotides 2000 and 2340, and epi-ADNP-2 mutations located between nucleotides 2000 and 2340. The episignatures were enriched for genes involved in neuronal system development and function. Bend et al. (2019) showed that the DNA methylation signatures could aid in diagnosis.

Breen et al. (2020) evaluated gene expression in 17 individuals with HVDAS and 19 controls to determine if gene expression changes were predictable based on methylation status. Profound alterations in corresponding gene expression profiles were not observed. The absence of correlation between methylation and gene expression signatures and clinical manifestations led Breen et al. (2020) to caution against making phenotypic assumptions based on the blood-based methylation profile.

In a worldwide cohort of 78 patients with HVDAS, Van Dijck et al. (2019) found that patients with a Y719X mutation (611386.0005, 611386.0009, and 611386.0011) were more severely affected compared to patients with other mutations. They walked later and had a higher pain threshold.

Breen et al. (2020) found that HVDAS patients with class I mutations (located outside nucleotides 2000 and 2340) and those with class II mutations (located between nucleotides 2000 and 2340) in the ADNP gene had similar frequencies of impaired intellectual development, language impairment, attention deficit-hyperactivity disorder, and other medical problems. Individuals with class II mutations had a significantly longer delay in first walking independently, a higher prevalence of ASD, and a tendency toward increased self-injurious behavior.