Contribution of uniparental disomy in a clinical trio exome cohort of 2675 patients

Wang, Lei; Liu, Pengfei; Bi, Weimin; Sim, Teresa; Wang, Xia; Walkiewicz, M.; Leduc, Magalie S.; Meng, Linyan; Xia, Fan; Eng, Christine M.; Yang, Yaping; Yuan, Bo; Dai, Hongzheng

doi:10.1002/mgg3.1792

Cited by 8 publications

(2 citation statements)

References 19 publications

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“…Investigating 214,915 trios, from the 23andMe sequencing dataset, representing a non-clinical general population, the authors found 105 cases of UPD estimating that UPD occurs with an overall prevalence rate of roughly 1 in 2000 births or 0.05% 103 . The frequency of UPDs found in studies that used exome sequencing of patient-parent trios of large clinical populations for all sorts of genetic conditions is higher and oscillates between 0.2 and 0.6% 104 – 106 . The investigation for UPDs with whole genome sequencing of 164 parent–child trios in a more selected cohort, an Irish cohort with rare disorders, found 3 UPDs a frequency of 1.8% 105 .…”

Section: Discussionmentioning

confidence: 97%

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD

Chaves,

Ocampos,

Barbato

et al. 2024

Sci Rep

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Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3–4% of the world’s population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan HD (41%) or 750K (59%) platforms in 1012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs, comprising 132 deletions and 74 duplications, interpreted as pathogenic, were found in 17% of the patients in the cohort and across all chromosomes. Additionally, 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one clinical phenotype, if not the main reason for referral to testing, for about one-third of the cohort, and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8–21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only for their potential pathogenic significance but were also explored to identify common LCSH in the South Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals for CMA were developmental delay (56%), ID (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here, we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.

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Section: Discussionmentioning

confidence: 97%

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD

Chaves,

Ocampos,

Barbato

et al. 2024

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Investigating 214,915 trios, from the 23andMe sequencing dataset, representing a nonclinical general population, the authors found 105 cases of UPD estimating that UPD occurs with an overall prevalence rate of roughly 1 in 2,000 births or 0,05% [98]. The frequency of UPDs found in studies that used exome sequencing of patient-parent trios of large clinical populations for all sorts of genetic conditions is higher and oscillates between 0,2 and 0,6% [99][100][101]. The investigation for UPDs with whole genome sequencing of 164 parent-child trios in a more selected cohort, an Irish cohort with rare disorders, found 3 UPDs a frequency of 1.8% [100].…”

Section: Lcshsmentioning

confidence: 99%

A Cohort Study of Individuals with Neurodevelopmental Disorders and/or Congenital Anomalies Investigated by High- Resolution Chromosomal Microarrays in Southern Brazil: The Significance of Autism Spectrum Disorder

Chaves,

Ocampos,

Barbato

et al. 2023

Preprint

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Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3–4% of the world’s population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan®HD (41%) or 750K (59%) platforms in 1,012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs were interpreted as pathogenic, including 132 deletions and 74 duplications, were found in 17% of the patients of the cohort and across all chromosomes. Further 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one of the clinical phenotypes, when not the main reason for referral to testing, for about one-third of the cohort and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8–21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only in the context of their potential pathogenic significance but were also explored to identify common LCSH in the south Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals to the CMA were developmental delay (56%), DI (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.

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Exome Sequencing Detects Uniparental Disomy of Chromosome 4 Revealing a LARP7 Pathogenic Variant Responsible for Alazami Syndrome: A Case Report

Amélie,

Julien,

Kevin

et al. 2024

American J of Med Genetics Pt A

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Alazami syndrome is an autosomal recessive disease characterized by global developmental delay, growth restriction, and distinctive facial features. Fewer than 50 individuals are currently reported with biallelic loss of function variants in LARP7. We report the case of a 3.5‐year‐old boy born from nonconsanguineous parents, presenting with syndromic global developmental delay. Exome sequencing identified a homozygous frameshift pathogenic variant in LARP7. Parental analysis failed to detect the variant in the paternal sample, although the father's biological paternity was confirmed. Targeted secondary bioinformatic analyses at the LARP7 locus suggested a 45 Mb loss of heterozygosity (LOH), further confirmed by a single nucleotide polymorphism array that identified four LOH regions on chromosome 4, including one encompassing LARP7. This LOH exposes the recessive LARP7 pathogenic variant, resulting in the manifestation of Alazami syndrome. To our knowledge, this is the first reported case of Alazami syndrome due to uniparental disomy (UPD). UPD is a rare cause of autosomal recessive disorders. Its identification is crucial for genetic counseling to adjust recurrence risk for siblings. This case highlights the effectiveness and usefulness of bioinformatics algorithms applied to next generation sequencing in detecting such events.

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Contribution of uniparental disomy in a clinical trio exome cohort of 2675 patients

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 8 publications

References 19 publications

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD

A Cohort Study of Individuals with Neurodevelopmental Disorders and/or Congenital Anomalies Investigated by High- Resolution Chromosomal Microarrays in Southern Brazil: The Significance of Autism Spectrum Disorder

Exome Sequencing Detects Uniparental Disomy of Chromosome 4 Revealing a LARP7 Pathogenic Variant Responsible for Alazami Syndrome: A Case Report

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