Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations

The germline mutation rate has been extensively studied and has been found to vary greatly between species, but much less is known about the somatic mutation rate in multicellular organisms, which remains very difficult to determine. Here, we present data on somatic mutation rates in mice and humans, obtained by sequencing single cells and clones derived from primary fibroblasts, which allows us to make the first direct comparison with germline mutation rates in these two species. The results indicate that the somatic mutation rate is almost two orders of magnitude higher than the germline mutation rate and that both mutation rates are significantly higher in mice than in humans. Our findings demonstrate both the privileged status of germline genome integrity and species-specific differences in genome maintenance.

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“…13 and mutations reported in ref. 14; data on germline mutation frequency in mice was obtained using sequencing data from ref.…”

Section: Resultsmentioning

confidence: 94%

Differences between germline and somatic mutation rates in humans and mice

et al. 2017

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“…The phenotypical variability, even within the same mouse strain, as in monozygotic twins with 22q11.2DS 29 , is also consistent with the role of stochastic effects, and potentially epigenetic and other mechanisms. It can be anticipated that ongoing genome-wide association, whole-genome sequencing and expression studies will identify genetic modifiers and mechanisms 73,74,105,124,227,228 .…”

Section: Discussionmentioning

confidence: 99%

22q11.2 deletion syndrome

McDonald‐McGinn

Sullivan

Marino

et al. 2015

Nat Rev Dis Primers

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1,131

1,133

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22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.

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“…Despite millions of people affected with rare diseases, connecting families with the same diagnosis can be a challenge as affected individuals can span national and international borders. The continued integration of genomic sequencing into clinical practice is inevitably leading to the identification of cases that expand previously described "classic" phenotypes (Chung et al 2015;Moortgat et al 2018;Toledo and Dahia 2015). Connecting families with shared genetic etiologies can create valuable scientific resources to understand the natural history of diseases, and centralized registries can aid in recruitment for studies of rare disorders.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotypic spectrum associated with OPHN1 variants

Schwartz¹,

Wojcik²,

Pelletier³

et al. 2019

European Journal of Medical Genetics

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Genomic sequencing has allowed for the characterization of new gene-to-disease relationships, as well as the identification of variants in established disease genes in patients who do not fit the classically-described phenotype. This is especially true in rare syndromes where the clinical spectrum is not fully known. After a lengthy and costly diagnostic odyssey, patients with atypical presentations may be left with many questions even after a genetic diagnosis is identified. We present a 22-year old male with hypotonia, developmental delay, seizure disorder, and dysmorphic facial features who enrolled in our rare disease research center at 18 years of age, where exome sequencing revealed a novel, likely pathogenic variant in the OPHN1 gene. Through efforts by the study team and collaborations with the larger genetics community, contacts with other families with OPHN1 variants were eventually made, and outreach by these families expanded the patient network. This partnership between families and researchers facilitated the gathering of phenotypic information, allowing for comparison of clinical presentations among three new patients and those previously reported in the literature. These comparisons found previously unreported commonalities between the newly identified patients, such as the presence of otitis media and the lack of genitourinary abnormalities (i.e. hypoplastic scrotum, microphallus, cryptorchidism), which had been noted to be classic features of patients with OPHN1 variants. As genomic sequencing becomes more common, connecting patients with novel variants in the same gene will facilitate phenotypic analysis and continue to refine the clinical spectrum associated with that gene.

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Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations

Cited by 19 publications

References 82 publications

Differences between germline and somatic mutation rates in humans and mice

Differences between germline and somatic mutation rates in humans and mice

22q11.2 deletion syndrome

Expanding the phenotypic spectrum associated with OPHN1 variants

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