ClinVar Genomic variation as it relates to human health

This mutation has been described in the literature as disease-causing and has been identified once in our laboratory as a de novo mutation in a 17-year-old male with intellectual disability, dysmorphic features, short stature, microcephaly, and obesity

ADNP frameshift variants are known to be pathogenic and multiple frameshift variants in this region have been reported in patients with Helsmoortel-van der Aa syndrome (PMID: 29724491, 24531329). This variant has been reported to occur de novo in multiple individuals with clinical features associated with this gene (PMID:24531329, 28221363, 32275126). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 271 amino acids are lost and replaced with 80 incorrect amino acids (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26845106, 29724491, 24531329, 24866042, 25533962, 28191890, 30107084, 28221363, 29911927, 28135719, 32275126, 32758449, 31526516, 32719394, 31785789, 33004838, 25326635)

This variant was identified as de novo (maternity and paternity confirmed).

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000139632 / PMID: 24531329). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change creates a premature translational stop signal (p.Asn832Lysfs*81) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 271 amino acid(s) of the ADNP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of Helsmoortel-Van der Aa syndrome (PMID: 24531329, 28221363, 32275126; Invitae). ClinVar contains an entry for this variant (Variation ID: 139632). For these reasons, this variant has been classified as Pathogenic.

Variant summary: ADNP c.2496_2499delTAAA (p.Asn832LysfsX81) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant was absent in 251334 control chromosomes (gnomAD). c.2496_2499delTAAA has been reported in the literature as a de denovo occurrence in multiple individuals affected with Helsmoortel-Van Der Aa Syndrome and autism spectrum disorder with developmental delay (examples: Helsmoortel_2014, Gozes_2017, Krgovic_2022, Maron_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37432431, 24531329, 35813072, 28221363). ClinVar contains an entry for this variant (Variation ID: 139632). Based on the evidence outlined above, the variant was classified as pathogenic.

The c.2496_2499delTAAA (p.N832Kfs*81) alteration, located in exon 5 (coding exon 3) of the ADNP gene, consists of a deletion of 4 nucleotides from position 2496 to 2499, causing a translational frameshift with a predicted alternate stop codon after 81 amino acids. This alteration occurs at the 3' terminus of the ADNP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 24.5% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected as a de novo occurrence in multiple individuals with neurodevelopmental disorders (Helsmoortel, 2014; Gozes, 2017; Van Dijck, 2019; Shillington, 2020). Functional analysis was performed using immunolabeling of the well-established heterochromatin marker HP1α to verify co-localization of ADNP with heterochromatin. While the p.N832Kfs*81 alteration co-localized with HP1, researchers noted that specific enrichment at pericentromeric heterochromatin seemed partially lost (Cappuyns, 2018). Based on the available evidence, this alteration is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Helsmoortel-van der Aa syndrome (MIM#615873) (PMID: 29911927). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten other individuals with ADNP-related disorder and consistently classified as pathogenic by diagnostic laboratories in ClinVar (DECIPHER; PMID: 32275126, 29724491, 24531329). (SP) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-07-02 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.

All other pathogenic variants are heterozygous frameshift or nonsense variants in the 3-prime end of 5th (last) exon of ADNP and predict a premature termination