Dataset Information

Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases.

ABSTRACT:

Introduction

Exome sequencing is recognized as a powerful tool for identifying the genetic cause of intellectual disability (ID). It is uncertain, however, whether only the exome of the proband should be sequenced or if the sequencing of parental genomes is also required, and the resulting increase in diagnostic yield justifies the increase in costs.

Patients and methods

We sequenced the exomes of eight individuals with sporadic syndromic ID and their parents.

Results and discussion

Likely pathogenic variants were detected in eight candidate genes, namely homozygous or compound heterozygous variants in three autosomal genes (ADAMTSL2, NALCN, VPS13B), one in an X-linked gene (MID1), and de novo heterozygous variants in four autosomal genes (RYR2, GABBR2, CDK13, DDX3X). Two patients harbored rare variants in two or more candidate genes, while in three other patients no candidate was identified. In five probands (62%), the detected variants explained their clinical findings. The causative recessive variants would have led to diagnosis even without parental exome sequencing, but for the heterozygous dominant ones, the exome trio-based approach was fundamental in the identification of the de novo likely pathogenic variants.

SUBMITTER: Carneiro TN

PROVIDER: S-EPMC6110279 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases.

Carneiro Thaise Nr TN Krepischi Ana Cv AC Costa Silvia S SS Tojal da Silva Israel I Vianna-Morgante Angela M AM Valieris Renan R Ezquina Suzana Am SA Bertola Debora R DR Otto Paulo A PA Rosenberg Carla C

The application of clinical genetics 20180822

<h4>Introduction</h4>Exome sequencing is recognized as a powerful tool for identifying the genetic cause of intellectual disability (ID). It is uncertain, however, whether only the exome of the proband should be sequenced or if the sequencing of parental genomes is also required, and the resulting increase in diagnostic yield justifies the increase in costs.<h4>Patients and methods</h4>We sequenced the exomes of eight individuals with sporadic syndromic ID and their parents.<h4>Results and discu ...[more]

PMID: 30174453

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Project description:BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. METHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. RESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G?>?C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. CONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.

Project description:BackgroundNon-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members.MethodsFamily members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton™ System. Validation of identified variants was performed with Sanger sequencing.ResultsThe linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders.ConclusionsDNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.

Project description:Understanding the genetic basis of developmental delay (DD) and intellectual disability (ID) remains a considerable clinical challenge. This study evaluated the clinical application of trio whole exome sequencing (WES) in children diagnosed with DD/ID. The study comprised 173 children with unexplained DD/ID. The participants underwent trio-WES and their demographic, clinical, and genetic characteristics were evaluated. Based on their clinical features, the participants were classified into two groups for further analysis: a syndromic DD/ID group and a non-syndromic DD/ID group. The genetic diagnostic yield of the 173 children diagnosed with DD/ID was 49.7% (86/173). This included 58 pathogenic or likely pathogenic single nucleotide variants (SNVs) in 41 genes identified across 54 individuals (31.2%) through trio-WES. Among these, 22 SNVs had not been previously reported. Additionally, 30 copy number variations (CNVs) were detected in 36 individuals (20.8%). The diagnostic yield in the syndromic DD/ID group was higher than that in the non-syndromic DD/ID group (57.8% vs. 47.2%, P < 0.001). Within the syndromic DD/ID subgroup, the diagnostic yield of the DD/ID with epilepsy subgroup (83.9%) was significantly higher than those of the other subgroups (P < 0.001). Based on the analysis of the individuals' clinical phenotypes, the individuals with facial dysmorphism shown a higher diagnostic yield (68.2%, P < 0.001). The diagnostic yield of SNVs was higher in the individuals with DD/ID accompanied by epilepsy, whereas the diagnostic yield of CNVs was higher in the DD/ID without epilepsy group. Similarly, the diagnostic yield of de novo SNVs was higher in the DD/ID with epilepsy group, while the diagnostic yield of de novo CNVs was higher in the DD/ID without epilepsy group (all P < 0.001). Trio-WES is a crucial tool for the genetic diagnosis of DD/ID, demonstrating a diagnostic yield of up to 49.7%. De novo variants in autosomal dominant genes are significant contributors to DD/ID, particularly in non-consanguineous families.

Dataset Information

Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases.

Introduction

Patients and methods

Results and discussion

Publications

Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases.

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