Novel features of Helsmoortel–Van der Aa/ADNP syndrome in a boy with a known pathogenic mutation in the <i>ADNP</i> gene detected by exome sequencing

Li, Chumei; Wang, Yongdong; Szybowska, Marta

doi:10.1002/ajmg.a.38201

Cited by 6 publications

(6 citation statements)

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“…Unlike the broader ASD population, among which ID is noted in approximately 30% of U.S. cases (D.D.M.N.S.Y., 2014), ID is a consistent (100%) finding in individuals reported to have a de novo ADNP mutation (Helsmoortel et al, 2014; Vandeweyer et al, 2014; Li, Wang & Szybowska, 2017), and some individuals are nonverbal. Functional gene classes associated with ASD- and ID-linked genes overlap substantially, suggesting that phenotypic expression depends on a number of factors including location and effect of the variant, and genetic and environmental interactions (Iossifov et al, 2014).…”

Section: Introductionmentioning

confidence: 95%

“…Critically, this sample was ascertained primarily for a diagnosis of ASD or intellectual disability (ID); thus, rates of ASD symptoms are expected to be biased. In contrast, fewer than 70% of a large international cohort of ADNP cases (ascertained via previous publication in genetic literature or via a parents’ social media network) carried an ASD diagnosis (Van Dijck et al, Under Review) and a recent case report has highlighted lack of ASD features in at least one affected child (Li, Wang & Szybowska, 2017). To address the ascertainment bias, our laboratory has employed a “genetics-first” approach, wherein participants are recruited primarily for a known disruptive mutation to ADNP and/or other ASD-linked genes.…”

Section: Introductionmentioning

confidence: 99%

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The autism spectrum phenotype in ADNP syndrome

et al. 2018

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Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res 2018, 11: 1300-1310. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The autism spectrum phenotype in ADNP syndrome

et al. 2018

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“…Helsmoortel-van der Aa (MIM #615873), a novel recognizable intellectual disability syndrome with autism comorbidity, is a monogenic autosomal dominant disorder caused by de novo frameshift or nonsense sequence alterations in the 3′ end of the last exon of ADNP [1]. All individuals with Helsmoortel-van der Aa syndrome had consistent clinical features, including autism spectrum disorders, mild to severe intellectual disability, and distinctive facial dysmorphism [2]. ADNP (MIM* 611386) is composed of five exons and encodes an activity-dependent neuroprotective homeobox protein.…”

Section: Introductionmentioning

confidence: 99%

A heterozygous microdeletion of 20q13.13 encompassing ADNP gene in a child with Helsmoortel–van der Aa syndrome

et al. 2018

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Helsmoortel-van der Aa (SWI/SNF autism-related or ADNP syndrome) is an autosomal dominant monogenic syndrome caused by de novo variants in the last exon of ADNP gene and no deletions have been documented to date. We report the first case of a 3 years and 10 months old boy exhibiting typical features of ADNP syndrome, including intellectual disability, autistic traits, facial dysmorphism, hyperlaxity, mood disorder, behavioral problems, and severe chronic constipation. 60K Agilent array-comparative genomic hybridization (CGH) identified a heterozygous interstitial microdeletion at 20q13.13 chromosome region, encompassing ADNP and DPM1. Taking into account the clinical phenotype of previously reported cases with ADNP single-point variants, genotype-phenotype correlation in the proband was established and the diagnosis of Helsmoortel-van der Aa syndrome was made. Our report thus confirms that ADNP haploinsufficiency is associated with Helsmoortel-van der Aa syndrome as well as highlights the utility of whole-genome array-CGH for detection of unbalanced submicroscopic chromosomal rearrangements in routine clinical setting in patients with unexplained intellectual disability and/or syndromic autism.

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“…In the last years, patients presenting pathogenic variants in the ADNP gene have been more studied due to the influence of the gene in ASD [13]. Although case reports describing this syndrome are still scarce, most of them describe HVDAS patients with signs and symptoms similar to those found in our patient: behavioral problems, autism spectrum, dysmorphic craniofacial features, constipation, global development delay and hypotonia [14][15][16][17].…”

Section: Discussionmentioning

confidence: 68%

Patient with Helsmoortel-van der Aa Syndrome and O’Donnell-Luria-Rodan Syndrome: a case report

Medeiros,

Coutinho,

Alarcón

et al. 2023

BJCR

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Heterozygous pathogenic variants in the ADNP gene cause Helsmoortel-van der Aa syndrome which is an autosomal dominant mutation, whose patients have autism spectrum disorder (ASD) and intellectual disability. Pathogenic variants in the KTM2E gene are related to O’Donnell-Luria-Rodan syndrome, also autosomal dominant, characterized by global development delay. The case of a male patient, only child, born at term measuring 45 cm (z-1) and weighing 2.460 kg (z-2) was described. The patient presented short stature, autism spectrum disorder, delay in neuropsychomotor development, gastrointestinal reflux, hyperopia, recurrent infections, and constipation. The result from whole exome sequencing (WES) identified two variants of uncertain significance (VUS) in the ADNP and KMT2E genes, whose syndrome related in literature have compatible signs and symptoms with those found in the patient.

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Novel features of Helsmoortel–Van der Aa/ADNP syndrome in a boy with a known pathogenic mutation in the ADNP gene detected by exome sequencing

Cited by 6 publications

References 3 publications

The autism spectrum phenotype in ADNP syndrome

The autism spectrum phenotype in ADNP syndrome

A heterozygous microdeletion of 20q13.13 encompassing ADNP gene in a child with Helsmoortel–van der Aa syndrome

Patient with Helsmoortel-van der Aa Syndrome and O’Donnell-Luria-Rodan Syndrome: a case report

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