Pathogenic paternally inherited <scp><i>NLGN4X</i></scp> deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Kopp, Nathan; Amarillo, Ina; Martinez‐Agosto, Julian A.; Quintero‐Rivera, Fabiola

doi:10.1002/ajmg.a.62025

Cited by 6 publications

(4 citation statements)

References 35 publications

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“…Another major difference between these tools lies in the detection of in-frame insertions/deletions that comprised ~ 20% of the variants detected by either InterVar or TAPES, while such SNVs were discarded by Psi-Variant. We decided to exclude these variants from Psi-Variant because their clinical relevance has been demonstrated in several genetic disorders 38,39 but not in ASD [40][41][42] .…”

Section: Discussionmentioning

confidence: 99%

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Shil,

Levin,

Golan

et al. 2023

Sci Rep

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Autism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole-exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single-nucleotide variants (SNVs) and short insertions/deletions (INDELs). However, interpreting these variants' functional and clinical consequences requires integrating multifaceted genomic information. We compared the concordance and effectiveness of three bioinformatics tools in detecting ASD candidate variants (SNVs and short INDELs) from WES data of 220 ASD family trios registered in the National Autism Database of Israel. We studied only rare (< 1% population frequency) proband-specific variants. According to the American College of Medical Genetics (ACMG) guidelines, the pathogenicity of variants was evaluated by the InterVar and TAPES tools. In addition, likely gene-disrupting (LGD) variants were detected based on an in-house bioinformatics tool, Psi-Variant, that integrates results from seven in-silico prediction tools. Overall, 372 variants in 311 genes distributed in 168 probands were detected by these tools. The overlap between the tools was 64.1, 22.9, and 23.1% for InterVar–TAPES, InterVar–Psi-Variant, and TAPES–Psi-Variant, respectively. The intersection between InterVar and Psi-Variant (I ∩ P) was the most effective approach in detecting variants in known ASD genes (PPV = 0.274; OR = 7.09, 95% CI = 3.92–12.22), while the union of InterVar and Psi Variant (I U P) achieved the highest diagnostic yield (20.5%).Our results suggest that integrating different variant interpretation approaches in detecting ASD candidate variants from WES data is superior to each approach alone. The inclusion of additional criteria could further improve the detection of ASD candidate variants.

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Section: Discussionmentioning

confidence: 99%

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Shil,

Levin,

Golan

et al. 2023

Sci Rep

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“…Neuroligins ( NLGNs ) are postsynaptic cell adhesion molecules that have critical functions in synapse maturation, and NLGNs are located on the human X chromosome, which is called NLGN4X [ 15 ]. It has been demonstrated that variants in NLGN4X are a potential pathogenic mechanism for male bias in autism spectrum disorder [ 16 , 17 ]. Otherwise, partial duplication of the NLGN4X gene (Xp22.32) is related to cognitive deficits [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Prenatally detected six duplications at Xp22.33-p11.22: a case report

Zhang

et al. 2023

BMC Pregnancy Childbirth

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Background The discrepancy between the results of cytogenetics and the results of chromosome microarray analysis (CMA) has often led to confusion over genetic counselling for prenatal diagnosis. Case presentation The prenatal ultrasound results of a congenital heart defect (CHD) foetus displayed an apartial endocardial pad defect and permanently dilated coronary sinus and left superior vena cava at 21 weeks of gestation. Cytogenetic analysis, CMA, fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) with foetal cord blood samples were used to detect the genetic aetiology. Routine G-binding cytogenetic analysis showed normal karyotypes in both the foetus’ and parents’ blood samples. CMA results demonstrated that there were 53.973-Mb recurrent CNVs at Xp22.33-p11.22, as confirmed by MLPA assay. Conclusions Herein, we described the CNV of six duplications at Xp22.33-p11.22 and the 53.973 Mb duplication CNV that was not found in foetal cord blood samples by conventional cytogenetic methods, and it was confirmed by CMA and MLPA. Our novel findings will provide helpful information for prenatal diagnosis and genetic counselling for foetal CHDs.

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“…Another major difference between these tools lies in the detection of in-frame insertions/deletions that comprised ~20% of the SNVs detected by either InterVar or TAPES, while such SNVs were discarded by Psi-Variant. We decided to exclude these SNVs from Psi-Variant because their clinical relevance has been demonstrated in several genetic disorders [36,37] but not in ASD [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Shil

Levin

Golan

et al. 2023

Preprint

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Background Autism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single nucleotide variants (SNVs). However, interpreting the functional and clinical consequences of these variants requires integrating multifaceted genomic information. Methods We compared the effectiveness of three bioinformatics tools in detecting ASD candidate SNVs from WES data of 250 ASD family trios registered in the National Autism Database of Israel. We studied only rare (less than 1% population frequency), proband specific SNVs. The pathogenicity of SNVs, according to the American College of Medical Genetics (ACMG) guidelines, was evaluated by the InterVar and TAPES tools. In addition, likely gene disrupting (LGD) SNVs were detected based on an inhouse bioinformatics tool, designated PsiVariant, that integrates results from seven insilico prediction tools. We compared the effectiveness of these three approaches and their combinations in detecting SNVs in high confidence ASD genes. Results Overall, 605 SNVs in 499 genes distributed in 193 probands were detected by these tools. The overlap between the tools was 64.1%, 17.0%, and 21.6% for InterVar and TAPES, InterVar and PsiVariant, and TAPES and PsiVariant, respectively. The intersection between InterVar and PsiVariant (I and P) was the most effective approach in detecting ASD genes (OR = 5.38, 95% C.I. = 3.25 to 8.53). This combination detected 102 SNVs in 99 genes among 80 probands (approximate 36% diagnostic yield). Conclusions Our results suggest that integration of different variant interpretation approaches in detecting ASD candidate SNVs from WES data is superior to each approach alone. Inclusion of additional criteria could further improve the detection of ASD candidate variants.

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Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Cited by 6 publications

References 35 publications

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Prenatally detected six duplications at Xp22.33-p11.22: a case report

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

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