Comprehensive molecular testing in patients with high functioning autism spectrum disorder

Álvarez-Mora, María Isabel; Escalona, Rosa Calvo; Navarro, Olga Puig; Madrigal, Irene; Quintela, Inés; Amigo, Jorge; Martinez-Elurbe, Dei; Linder-Lucht, M; Laín, Gemma Aznar; Carracedo, Ángel; Milá, Montserrat; Rodríguez‐Revenga, Laia

doi:10.1016/j.mrfmmm.2015.12.006

Cited by 30 publications

(26 citation statements)

References 36 publications

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“…Given the nature of genetic selection, common gene variants that provide variable autism risk (i.e., common disease-common variant) are more likely to explain a wider breadth of cases than the rare, often de novo, mutations that confer higher penetrance for the phenotype. Although interestingly, a recent study by Alvarez-Mora et al [ 33 ] reported that in a subset of high-functioning cases they studied, over 50 % (6/11) of the identified rare potentially deleterious single nucleotide variants (SNV) occurred within the HCA genes reported here, suggesting that these genes may be targets with variable penetrance dependent upon the specific type of mutation. Sanders et al [ 34 ] have found that highly penetrant deleterious SNVs tend to affect the same genes that are also targets of small copy number variants (CNV) in autism, such as occurs in the monogenic conditions studied here.…”

Section: Discussionmentioning

confidence: 71%

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression

et al. 2016

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BackgroundIntellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities.MethodsUtilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk.ResultsThe genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS.ConclusionsAccording to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0082-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 71%

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression

et al. 2016

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“…The yield of targeted gene panels in the evaluation of individuals with ASD has not been well defined. There is one report from 2016 describing a yield of 13.6% for possibly contributory variants from testing of 50 Spanish children utilizing a 44 gene targeted panel (Alvarez‐Mora et al., ). Their criteria for defining a variant as relevant was based primarily on its predicted in silico pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications

Kalsner

Twachtman-Bassett

Tokarski

et al. 2017

Molec Gen & Gen Med

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BackgroundGenetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well.MethodsWe performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database.ResultsWe did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database.ConclusionThe yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large‐scale genomic databases used to identify variants that contribute to disease risk.

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“…Missense variants in ADNP have been associated with disease in the literature [24][25][26]. However, this evidence may be insufficient to establish missense variation as a mechanism for disease [1,4].…”

Section: Classification Of Subjects With An Uncertain Diagnosis Of Admentioning

confidence: 99%

Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome

et al. 2019

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Background: ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. Results: We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The "epi-ADNP-1" episignature included~6000 mostly hypomethylated CpGs, and the "epi-ADNP-2" episignature included~1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N-and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. Conclusions: We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome.

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Comprehensive molecular testing in patients with high functioning autism spectrum disorder

Cited by 30 publications

References 36 publications

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications

Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome

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