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

Abstract

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.

ADNP Regulates Cognition: A Multitasking Protein

“…Further results indicate microtubule insufficiency, reduced axonal transport (Amram et al, 2016 ) and reduced dendritic spines (Hacohen-Kleiman et al, 2018 ) in the Adnp +/− mice. These findings are in line with patient results showing intellectual disabilities in case of ADNP gene heterozygous microdeletion or truncating mutation (Borozdin et al, 2007 ; Vandeweyer et al, 2014 ; Huynh et al, 2018 ). Given the fact that ADNP is a large protein it includes many identified signature motifs for macromolecular interactions and here I will concentrate on the ADNP motifs, protein interactors and the strong link to cognition.…”

“…The direct involvement of ADNP in cognitive function was reported in our 2007 Adnp haploinsufficient mouse model (Vulih-Shultzman et al, 2007 ) coupled with a paper showing that deletion in the chromosomal area including ADNP [20q12–13.2 (Zamostiano et al, 2001 )] specifically, 20q13.13–q13.2 (Borozdin et al, 2007 ) resulted in developmental delays and intellectual disabilities in humans. Both animal studies (Malishkevich et al, 2015 ; Amram et al, 2016 ; Hacohen-Kleiman et al, 2018 ) as well as the human studies were repeated and extended showing axonal/synaptic/behavioral dysfunctions at the mouse level (Amram et al, 2016 ; Hacohen-Kleiman et al, 2018 ) mirroring the human situation when the ADNP gene is partially deleted (Huynh et al, 2018 ) or pathologically mutated (Helsmoortel et al, 2014 ; Vandeweyer et al, 2014 ; Gozes et al, 2015 , 2017a , b , 2018 ; Arnett et al, 2018 ; Van Dijck et al, 2018 ). Over the last 4 years it became apparent that the mutated ADNP gene is consistently reported as one of the most frequent causes of syndromic autism and intellectual disability (Helsmoortel et al, 2014 ; Larsen et al, 2016 ; Deciphering Developmental Disorders, 2017 ; Stessman et al, 2017 ).…”

The ADNP Syndrome and CP201 (NAP) Potential and Hope

“…Importantly, the mutated (mostly truncated) and the intact ADNP alleles are both expressed in ADNP syndrome human cells (4), supporting the Adnp +/− mouse as a model predictive for ADNP heterozygous mutation deficiency in humans (6,26). Furthermore, some children with ADNP syndrome show almost complete deletions of one allele (9), presenting a haploinsufficient loss-of-function phenotype (1,9). Finally, there is a very high conservation of the ADNP gene between human and mouse (about 90% identity at the mRNA level) (8), and ADNP is critical for brain development in the mouse, like in human (23).…”

“…The human ADNP gene is ∼40 kilobases long and contains five exons and four introns (5). The gene is located on the q13.13 band of chromosome 20 (8,9). The protein comprises 1,102 amino acids including asparagine-alanine-proline-valine-serine-isoleucine-proline-glutamine (NAPVSIPQ), which is an 8-amino-acid neuroprotective peptide called NAP (also discovered by the Gozes Laboratory).…”

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

“…Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome shift mutations (15,17,28), with some showing almost complete deletions of 1 allele (19,29), presenting a haploinsufficient genotype/phenotype. A comprehensive comparative analysis of 78 children with ADNP syndrome with mutations spanning the entire protein suggested a similar partial loss of function among the different phenotypic outcomes, with somewhat increased severity in children carrying the most abundant mutation p.Tyr719* (27).…”