Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Abstract

Background: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.

Methods: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.

Results: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.

Conclusions: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

Keywords: ADNP; Autism; Genetics; Helsmoortel-Van der Aa syndrome; Intellectual disability; Neurodevelopmental disorder.

Figure 1.

Schematic illustration of ADNP and its functional domains. ADNP consists of five exons and 14 domains, including nine zinc fingers, NAP (a short octapeptide sequence, single letter code, NAPVSIPQ), an eIF4E interaction motif, a nuclear localization signal (NLS), an alanine-arginine-lysine-serine (ARKS) motif, a DNA-binding homeobox domain, and a PxVxL motif (15,17,30). Zinc fingers: AA 74–97, 107–129, 165–188, 221–244, 447–469, 489–510, 512–535, 622–647, 662–686; NAP amino acid (AA) 354–361; eIF4E NAP AA 490–499; NLS AA 716–733; ARKS motif AA 765–768; DNA-binding homeobox domain AA 754–814; PxVxL heterochromatin protein 1 (HP1) interaction motif AA 819–823. Black arrows indicate the location of the mutations in the reported individuals, highlighting the three most frequent mutations.

Figure 2.

Demographic data of the reported individuals: (A) country of origin, (B) gender, and (C) age distribution.

Figure 3.

Clinical features reported in individuals with ADNP mutation: (A) cardiac abnormalities, (B) behavioral problems, (C) brain magnetic resonance imaging (MRI) abnormalities, (D) feeding and gastrointestinal problems, (E) visual problems, and (F) general health problems. ADHD, attention-deficit/ hyperactivity disorder.

Figure 4.

Facial features of individuals with mutations in ADNP. Frontal and lateral views. Note the prominent forehead with high anterior hairline, the wide and depressed nasal bridge, and short nose with full, upturned nasal tip. Informed consent has been obtained for publication of all images present in this paper. (Individual numbers from Supplemental Table S2 corresponding to the pictures: A = 49, B = 34, C = 44, D = 21, E = 17, F = 63, G = 28, H = 29, I = 45, J = 11, K = 38, L = 15, M = 48, N = 50, O = 60, P = 36, Q = 58, R = 33, S = 51, T = 39, U = 42, V = 31, W = 41, X = 10, Y = 70, Z = 27).

Figure 5.

Individuals at different ages showing evolution with age. (A) Individual 1 at 10 months, 15 months, 29 months, 4 years, and 6 years of age; (B) individual 32 at 13 months, 26 months, 3 years 10 months, 5 years 11 months, 5 years 11 months of age; (C) individual 40 at 4 months, 13 months, 13 months, 3 years 6 months, 3 years 6 months of age; (D) individual 65 at 3 months, 10 months, 24 months, 4 years 9 months, 8 years 9 months of age. Informed consent has been obtained for publication of all images present in this paper.

Figure 6.

Brain magnetic resonance imaging of a child with a mutation in the ADNP gene. (A) Brain magnetic resonance image of individual 49 performed at 13 months of age, showing generalized and frontal cortical atrophy and a gracile corpus callosum (sagittal, T2 weighted fluid-attenuated inversion recovery). (B) Brain magnetic resonance image of individual 49 performed at 19 months of age, showing frontotemporal atrophy (axial, T1-weighted). (C) Brain magnetic resonance image of individual 45 performed at 12 years of age, showing mild frontal atrophy (axial, T2-weighted).