Promising therapeutic aspects in human genetic imprinting disorders

Chao, Yunqi; Qin, Yifang; Zou, Xinyi; Wang, Xiangzhi; Hu, Chenxi; Xia, Fangling; Zou, Chaochun

doi:10.1186/s13148-022-01369-6

Cited by 4 publications

(3 citation statements)

References 141 publications

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“…Out of the 27 potential UPD cases identi ed in our study (Table 5 and Fig. 4), only seven were associated with chromosomes known for imprinting disorders [105]. Cases #169 and #346 on chromosome 7, as well as case #312 on chromosome 14, have been previously discussed [28].…”

Section: Lcshsmentioning

confidence: 78%

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.

show abstract

Section: Lcshsmentioning

confidence: 78%

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

View full text Add to dashboard Cite

show abstract

“…Out of the 27 potential UPD cases identified in our study (Table 5 and Fig. 4 ), only seven were associated with chromosomes known for imprinting disorders 110 . Cases #169 and #346 on chromosome 7, as well as case #312 on chromosome 14, have been previously discussed 28 .…”

Section: Discussionmentioning

confidence: 95%

“…In a complete UPD, whether it's isodisomic, iso/heterodisomic, or entirely heterodisomic, both homologous chromosomes will exhibit the gende-specific imprinting of the sole transmitting parent across their entire length. It's also important to remember that long, uninterrupted stretches of homozygosity may also result from homologous repair through a breakage-induced DNA replication mechanism, which, in contrast, can originate segmental UPDs 110 .…”

Section: Discussionmentioning

confidence: 99%

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

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.

show abstract

An overview of epigenetics of human disease

Tollefsbol

2024

Epigenetics in Human Disease

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Promising therapeutic aspects in human genetic imprinting disorders

Cited by 4 publications

References 141 publications

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

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

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

An overview of epigenetics of human disease

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