The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability

Harripaul, Ricardo; Noor, Abdul; Ayub, Muhammad; Vincent, John B.

doi:10.1101/cshperspect.a026864

Cited by 46 publications

(32 citation statements)

References 64 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, significant numbers of genes harboring de novo mutations are shared across different neurodevelopmental or neuropsychiatric disorders (Cukier et al, 2014;Vissers et al, 2010). Many genes have already been shown to cause both ID and/or ASD, including PTCHD1, SHANK3, NLGN4, NRXN1, CNTNAP2, UBE3A, FMR1, MECP2, and others (Harripaul, Noor, Ayub, & Vincent, 2017). Despite the apparent distinct pathogenesis for these disorders, analysis of network connectivity of the candidate genes revealed that many rare genetic alterations converge on a few key biological pathways (Krumm, O'Roak, Shendure, & Eichler, 2014;Vissers et al, 2010).…”

mentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

View full text Add to dashboard Cite

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low‐cost next‐generation sequencing gene panel that has been transferred into clinical practice, replacing single disease‐gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease‐gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease‐causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

show abstract

mentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

View full text Add to dashboard Cite

show abstract

“…On this basis, some scholars divide monogenic GDD/ID into ARID, ADID and XLID [9][10][11]. With the improvement of next-generation sequencing (NGS) [12], monogenic causes are being found in previously unexplained or idiopathic cases of GDD/ID. Some scholars estimated that the diagnostic yield of exome sequencing in neurodevelopmental delay was 36%, higher than the power of chromosomal microarray (CMA) testing (15-20%) [13].…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Characteristics and Prenatal Diagnosis of Rare Monogenic Global Developmental Delay and Intellectual Disability.

Lin¹,

Zhang²,

Pan³

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: The estimated worldwide prevalence of global developmental delay (GDD) and intellectual disability (ID) is 1-3%. Rare monogenic GDD/ID is poorly characterized because its low prevalence limits research. In this study, we aimed to describe the diagnostic courses and clinical and genetic characteristics of a cohort with rare monogenic GDD/ID.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectra of rare monogenic GDD/ID patients. We also conducted a follow-up study on prenatal diagnosis in these families. Mutation pathogenicity was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics. Results:Among 108 patients with rare monogenic GDD/ID, it often took 0.5-4 years and 3-5 referrals to obtain a genetic diagnosis after disease onset. Onset typically occurred before 6 years of age, and patients usually presented moderate to severe GDD/ID. The most common coexisting conditions were epilepsy (68%), facial dysmorphism (14%) and microcephaly (13%). In total, 149 different pathogenic variants were found in 81 different genes among the 108 pedigrees, and 71 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal recessive (AR; 46.3%), autosomal dominant (AD; 37%), and X-linked (XL; 16.7%). GLB1, PLA2G6, SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot mutations were rarely found. By the follow-up, 43 families, including 24 ARID, 13 ADID and 6 XLID families, had undergone prenatal diagnosis. The offspring of 6 ARID, 2 ADID and 2 XLID families had the same pathogenic variants as the probands.Conclusion:Rare monogenic GDD/ID is characterized by early onset, relatively severe symptoms, great clinical variability and genetic heterogeneity. Moreover, timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

show abstract

“…More than 66 genes are implicated in the pathogenesis of ARID (Hu et al, 2019). Advances in genetic diagnosis and high throughput technologies have enabled delineating phenotypes associated with each gene (Harripaul et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Bakhiet

Hamed

Abozar

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundAutosomal recessive intellectual disabilities, syndromic and non-syndromic, are of specific importance in consanguineous communities. High throughput sequencing technologies have enhanced diagnosing the Mendelian forms of intellectual disability. Mental retardation 36 and 38 are emerging clinical entities with variable presentations that extend beyond adaptive and intellectual functioning. MethodsWe used exome sequencing, bioinformatic tools and Sanger sequencing to diagnose two Sudanese families with syndromic intellectual disability. ResultsWe identified the variant NM_138422.3 (ADAT3):c.430G>A (rs730882213) in a homozygous state in two female siblings manifesting a clinical phenotype consistent with mental retardation 36. This variant was previously identified as pathogenic founder variant in multiple families from the Middle East manifesting mental retardation 36. Our patients had bullet-shaped distal phalanges, expanding the previously reported presentation. In a second family, the proband had a clinical phenotype consistent with mental retardation 38. Genetic analysis revealed the novel homozygous variant NM_004667.4 (HERC2):c.10855C>T as the potential culprit. In addition to what has been reported previously, the proband had cleft lip and palate, bulbous nose, spastic lower limbs and stones in his gallbladder.Conclusion Herein, we corroborated and extended the previously reported phenotypic spectrums associated with autosomal recessive mental retardation 36 and 38.

show abstract

The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability

Cited by 46 publications

References 64 publications

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

Clinical and Genetic Characteristics and Prenatal Diagnosis of Rare Monogenic Global Developmental Delay and Intellectual Disability.

Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Contact Info

Product

Resources

About