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

Abstract

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome‐wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.

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

“…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).…”

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

“…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.…”

“…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).…”