Pleiotropy between language impairment and broader behavioral disorders—an investigation of both common and rare genetic variants

Appadurai, Vivek; Buil, Alfonso; Nordentoft, Merete; Werge, Thomas

doi:10.1186/s11689-021-09403-z

Cited by 7 publications

(5 citation statements)

References 119 publications

(122 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Language plays a major part in the outcomes of ASD. ASD children whose language is impaired, could have a large impact on the social interaction and general wellbeing of individuals (Nudel et al, 2021). Improvements in the language of ASD children before 5 years old may result in catching up to overall average levels in developmental trajectories, whereas the remainders may develop ID (Pickles et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeted sequencing and clinical strategies in children with autism spectrum disorder: A cohort study

Wang

et al. 2023

Front. Genet.

View full text Add to dashboard Cite

Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with genetic and clinical heterogeneity. Owing to the advancement of sequencing technologies, an increasing number of ASD-related genes have been reported. We designed a targeted sequencing panel (TSP) for ASD based on next-generation sequencing (NGS) to provide clinical strategies for genetic testing of ASD and its subgroups.Methods: TSP comprised 568 ASD-related genes and analyzed both single nucleotide variations (SNVs) and copy number variations (CNVs). The Autism Diagnostic Observation Schedule (ADOS) and the Griffiths Mental Development Scales (GMDS) were performed with the consent of ASD parents. Additional medical information of the selected cases was recorded.Results: A total of 160 ASD children were enrolled in the cohort (male to female ratio 3.6:1). The total detection yield was 51.3% for TSP (82/160), among which SNVs and CNVs accounted for 45.6% (73/160) and 8.1% (13/160), respectively, with 4 children having both SNVs and CNV variants (2.5%). The detection rate of disease-associated variants in females (71.4%) was significantly higher than that in males (45.6%, p = 0.007). Pathogenic and likely pathogenic variants were detected in 16.9% (27/160) of the cases. SHANK3, KMT2A, and DLGAP2 were the most frequent variants among these patients. Eleven children had de novo SNVs, 2 of whom had de novo ASXL3 variants with mild global developmental delay (DD) and minor dysmorphic facial features besides autistic symptoms. Seventy-one children completed both ADOS and GMDS, of whom 51 had DD/intellectual disability (ID). In this subgroup of ASD children with DD/ID, we found that children with genetic abnormalities had lower language competence than those without positive genetic findings (p = 0.028). There was no correlation between the severity of ASD and positive genetic findings.Conclusion: Our study revealed the potential of TSP, with lower cost and more efficient genetic diagnosis. We recommended that ASD children with DD or ID, especially those with lower language competence, undergo genetic testing. More precise clinical phenotypes may help in the decision-making of patients with genetic testing.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In other words, children with lower language competence had a greater chance of finding genetic variants. Nudel et al (2021) considered it as pleiotropy between language impairment and ASD. They observed a significant genetic overlap between specific language impairment and childhood autism (which excluded Asperger's syndrome).…”

Section: Discussionmentioning

confidence: 99%

Targeted sequencing and clinical strategies in children with autism spectrum disorder: A cohort study

Wang

et al. 2023

Front. Genet.

View full text Add to dashboard Cite

show abstract

“…It is suggested that there may be multiple risk factors, which can reinforce each other, like chronic otitis media ( 5 ), socio-economic status ( 6 ), and oral-motor difficulties ( 7 ). As stated above, it is well known that language problems can co-occur with autism spectrum disorder ( 8 ), behavioral disorders ( 9 ) and certain epilepsy disorders ( 10 ). Furthermore, family and twin studies have indicated that DLD have a strong genetic component ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic outcomes in children with developmental language disorder: a systematic review

van Wijngaarden,

de Wilde,

Mink van der Molen

et al. 2024

Front. Pediatr.

View full text Add to dashboard Cite

IntroductionDevelopmental language disorder (DLD) is a common childhood condition negatively influencing communication and psychosocial development. An increasing number of pathogenic variants or chromosomal anomalies possibly related to DLD have been identified. To provide a base for accurate clinical genetic diagnostic work-up for DLD patients, understanding the specific genetic background is crucial. This study aims to give a systematic literature overview of pathogenic variants or chromosomal anomalies causative for DLD in children.MethodsWe conducted a systematic search in PubMed and Embase on available literature related to the genetic background of diagnosed DLD in children. Included papers were critically appraised before data extraction. An additional search in OMIM was performed to see if the described DLD genes are associated with a broader clinical spectrum.ResultsThe search resulted in 15,842 papers. After assessing eligibility, 47 studies remained, of which 25 studies related to sex chromosome aneuploidies and 15 papers concerned other chromosomal anomalies (SCAs) and/or Copy Number Variants (CNVs), including del15q13.1–13.3 and del16p11.2. The remaining 7 studies displayed a variety of gene variants. 45 (candidate) genes related to language development, including FOXP2, GRIN2A, ERC1, and ATP2C2. After an additional search in the OMIM database, 22 of these genes were associated with a genetic disorder with a broader clinical spectrum, including intellectual disability, epilepsy, and/or autism.ConclusionOur study illustrates that DLD can be related to SCAs and specific CNV's. The reported (candidate) genes (n = 45) in the latter category reflect the genetic heterogeneity and support DLD without any comorbidities and syndromic language disorder have an overlapping genetic etiology.

show abstract

“…Furthermore, disentangling the polygenic contribution in DLD is lagging compared to the monogenic forms. Few studies investigated the polygenic overlap between DLD and other NDD without identifying any major signi cant association (Dale et al, 2020;Nudel et al, 2021). A recent genome-wide association study (GWAS) identi ed a robust single nucleotide polymorphism (SNP) heritability of ve reading-and/or language-related traits, not including DLD, that explained 13-26% of traits variability (Eising et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2023

Preprint

View full text Add to dashboard Cite

Background Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Methods Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. Results We identified clinically significant variants in five probands, resulting in a 9.4% (5/53) molecular diagnostic yield. Those variants were in CHD3, PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. However, we detected positive associations between neurodevelopmental difficulties and PRS for educational attainment and cognitive performance within the families (p = 0.006 and 0.02, respectively). We did not detect significant associations between PRS for language quantitative measures and their corresponding PRS. Conclusion Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the conditions.

show abstract

Pleiotropy between language impairment and broader behavioral disorders—an investigation of both common and rare genetic variants

Cited by 7 publications

References 119 publications

Targeted sequencing and clinical strategies in children with autism spectrum disorder: A cohort study

Targeted sequencing and clinical strategies in children with autism spectrum disorder: A cohort study

Genetic outcomes in children with developmental language disorder: a systematic review

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Contact Info

Product

Resources

About