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SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay.

ABSTRACT: BACKGROUND: Molecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity (LOH), which can indicate the presence of a homozygous mutation or uniparental disomy. Since these abnormalities can be associated with ID and/or MCA, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection has not been established. METHODS: We selected 21 children affected with ID, with or without congenital malformations, for whom standard genetic analyses failed to provide a diagnosis. We performed high-resolution SNP array analysis with four platforms (Affymetrix Genome-Wide Human SNP Array 6.0, Affymetrix Cytogenetics Whole-Genome 2.7 M array, Illumina HumanOmni1-Quad BeadChip, and Illumina HumanCytoSNP-12 DNA Analysis BeadChip) on whole-blood samples obtained from children and their parents to detect pathogenic CNVs and LOHs, and compared the results with those obtained on a moderate resolution array-based comparative genomic hybridization platform (NimbleGen CGX-12 Cytogenetics Array), already used in the clinical setting. RESULTS: We identified a total of four pathogenic CNVs in three patients, and all arrays successfully detected them. With the SNP arrays, we also identified a LOH containing a gene associated with a recessive disorder consistent with the patient's phenotype (i.e., an informative LOH) in four children (including two siblings). A homozygous mutation within the informative LOH was found in three of these patients. Therefore, we were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs. CONCLUSIONS: This study shows the clinical usefulness of SNP arrays in children with ID, since they successfully detect pathogenic CNVs, identify informative LOHs that can lead to the diagnosis of a recessive disorder. It also highlights some challenges associated with the use of SNP arrays in a clinical laboratory.

SUBMITTER: D'Amours G

PROVIDER: S-EPMC4299176 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay.

D'Amours Guylaine G Langlois Mathieu M Mathonnet Géraldine G Fetni Raouf R Nizard Sonia S Srour Myriam M Tihy Frédérique F Phillips Michael S MS Michaud Jacques L JL Lemyre Emmanuelle E

BMC medical genomics 20141224

<h4>Background</h4>Molecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity ( ...[more]

PMID: 25539807

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Project description:ObjectivesEarly developmental assessment is crucial for effective support and intervention. This study examined factors that contribute to (a) older child age when caregivers first became concerned about their child's development and (b) older child age at the point of entry into developmental and diagnostic assessment. We also quantified how factors contributed to risk of children not receiving an assessment by 5 years and considered the acceptability of electronic data capture for families.DesignThis cross-sectional study collected information about caregiver developmental concerns, family history and child characteristics.SettingChildren and families entered a large, publicly funded hospital-based paediatric developmental assessment service.ParticipantsConsecutively enrolled children (N=916) aged 6 months to 17 years with neurodevelopmental concerns and their caregivers.Main outcomes and measuresA developmental history questionnaire completed by caregivers.ResultsThe average age that caregivers identified developmental concerns was 3.0 years of age but the average age of a receiving a developmental assessment was 6.6 years. Only 46.4% of children received a diagnostic assessment by 5 years of age, even though 88.0% of caregivers were concerned about their child's development by that age. Parental age, relationship status, education level, prior use of support services and being from a culturally and linguistically diverse background contributed to age at identification of concern, age at diagnostic assessment and the likelihood of receiving a diagnostic assessment by 5 years. Electronic data capture had high acceptability, with 88.2% of caregivers reporting a preference for electronic completion of questionnaires.ConclusionsThe study shows a substantial delay in diagnostic assessments that leaves most vulnerable children without an assessment by school age and highlights contributors to delays. These delays highlight the complexity of delivering early intervention and support policies that rely on swift and appropriate developmental assessment to vulnerable families.

Project description:BackgroundGlobal developmental delay or intellectual disability usually accompanies various genetic disorders as a part of the syndrome, which may include seizures, autism spectrum disorder and multiple congenital abnormalities. Next-generation sequencing (NGS) techniques have improved the identification of pathogenic variants and genes related to developmental delay. This study aimed to evaluate the yield of whole exome sequencing (WES) and neurodevelopmental disorder gene panel sequencing in a pediatric cohort from Ukraine. Additionally, the study computationally predicted the effect of variants of uncertain significance (VUS) based on recently published genetic data from the country's healthy population.MethodsThe study retrospectively analyzed WES or gene panel sequencing findings of 417 children with global developmental delay, intellectual disability, and/or other symptoms. Variants of uncertain significance were annotated using CADD-Phred and SIFT prediction scores, and their frequency in the healthy population of Ukraine was estimated.ResultsA definitive molecular diagnosis was established in 66 (15.8%) of the individuals. WES diagnosed 22 out of 37 cases (59.4%), while the neurodevelopmental gene panel identified 44 definitive diagnoses among the 380 tested patients (12.1%). Non-diagnostic findings (VUS and carrier) were reported in 350 (83.2%) individuals. The most frequently diagnosed conditions were developmental and epileptic encephalopathies associated with severe epilepsy and GDD/ID (associated genes ARX, CDKL5, STXBP1, KCNQ2, SCN2A, KCNT1, KCNA2). Additionally, we annotated 221 VUS classified as potentially damaging, AD or X-linked, potentially increasing the diagnostic yield by 30%, but 18 of these variants were present in the healthy population of Ukraine.ConclusionsThis is the first comprehensive study on genetic causes of GDD/ID conducted in Ukraine. This study provides the first comprehensive investigation of the genetic causes of GDD/ID in Ukraine. It presents a substantial dataset of diagnosed genetic conditions associated with GDD/ID. The results support the utilization of NGS gene panels and WES as first-line diagnostic tools for GDD/ID cases, particularly in resource-limited settings. A comprehensive approach to resolving VUS, including computational effect prediction, population frequency analysis, and phenotype assessment, can aid in further reclassification of deleterious VUS and guide further testing in families.

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SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay.

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SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay.

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