Clinical characterization of individuals with the distal 1q21.1 microdeletion

Edwards, Stacey D.; Schulze, Katharina; Rosenfeld, Jill A.; Westerfield, Lauren; Gerard, Amanda; Yuan, Bo; Grigorenko, Elena L.; Posey, Jennifer E.; Bi, Weimin; Liu, Pengfei

doi:10.1002/ajmg.a.62104

Cited by 12 publications

(3 citation statements)

References 51 publications

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“…IUGR was frequently described in microdeletion and microduplication cases ascertained prenatally in this cohort (12.5% and 8.3% respectively), whereas it was not commonly described in the literature (1.8% and 1.1% respectively). In a recent review of 1q21.1 microdeletions, Edwards et al (Edwards et al, 2021) observed five subjects with a history of IUGR and four with oligohydramnios, similar to one of the microdeletion cases (patient 26) in this cohort. It is worth noting that in previous reports, most of the pregnancies were terminated (62.5% and 71.4% of pregnancies with deletions and duplications, respectively).…”

Section: Discussionsupporting

confidence: 66%

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review

Bourgois,

Bizaoui,

Colson

et al. 2023

American J of Med Genetics Pt A

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Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long‐term follow‐up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis.

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Section: Discussionsupporting

confidence: 66%

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review

Bourgois,

Bizaoui,

Colson

et al. 2023

American J of Med Genetics Pt A

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“…It may have been challenging to collect a cohort of patients with large recurrent deletions two decades ago, but advancements in clinical testing and populational screening have made such a genomic experimental effort feasible now, either from large diagnostic centers or from clinical registries. 17 ; 22 ; 28 ; 51 ; 52 ; 62 ; 63 Even when available subject numbers are limited for recurrent genomic deletions with extremely low penetrance, it is possible to tune the disease gene/allele characterization strategy by targeting specific phenotypes, as demonstrated at the Smith Magenis Syndrome - MYO15 locus two decades ago. 64 While researchers are starting to sequence cohorts of individuals with large deletions, 13 ; 65 it is imperative for clinical and diagnostic genomicists to foster guidelines that facilitate routine genomic sequencing (ES or WGS) on patients who are found to have recurrent genomic deletions, which will benefit both the patients and the research field.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, this approach requires prior knowledge and screening of individuals for the recurrent deletion CNVs. It may have been challenging to collect a cohort of patients with large recurrent deletions two decades ago, but the ‘clinical awareness’ of genomic disorders (Lupski 2021; Lupski 2022), advancements in clinical testing and populational screening have made such a genomic experimental effort feasible, either from large diagnostic centers or from clinical registries (Weiss et al 2008; Shinawi et al 2010; Mannik et al 2015; Dewey et al 2016; Crawford et al 2019; Jonch et al 2019; Edwards et al 2021). Even when available subject numbers are limited for recurrent genomic deletion CNVs with extremely low penetrance, it is possible to tune the disease gene/allele characterization strategy by targeting specific phenotypes, as demonstrated at the Smith Magenis Syndrome - MYO15 locus two decades ago (Liburd et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Yuan

Schulze

Batzir

et al. 2021

Preprint

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In medical genetics, discovery and characterization of new "disease genes" and alleles depend on patient ascertainment strategies to enrich previously uncharacterized alleles. Here, we present a novel strategy of new allele and gene discovery for recessive/biallelic disease traits. In this approach, patients with large recurrent genomic deletions mediated by nonallelic homologous recombination (NAHR) are sequenced, and new discoveries are revealed in the hemizygous chromosomal regions in trans to the large deletion, essentially enabling haploid genomic segment genetics. We demonstrate through computational analyses that a collection of 30 large recurrent genomic deletions scattered in the human genome contribute to more than 10% of individual disease load for 2.13% of all known "recessive disease genes". We performed meta-analyses for all literature reported patients affected with the 13 genes whose carrier burden are predicted to be almost exclusively from large recurrent genomic deletions. The results suggest that current sequencing efforts for personal genomes with large recurrent deletions is under-appreciated. By retrospective analyses of previously undiagnostic exome sequencing (ES) data on 69 subjects harboring 26 types of recurrent deletions, probable diagnostic variants were uncovered in genes including COX10, ERCC6, PRRT2 and OTUD7A, demonstrating new disease allele/gene/mechanism characterization. Findings from this study support the contention that more whole genome sequencing (WGS) may further resolve molecular diagnoses and provide evidence for multi-locus pathogenic variation (MPV). Such analyses benefit all stakeholders in both research development and patient clinical care.

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