Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study

Elliott, Alison M; Adam, Shelin; Souich, Christèle du; Lehman, Anna; Nelson, Tanya N.; Alderman, Emily; Armstrong, Linlea; Aubertin, Gudrun; Blood, Katherine; Boelman, Cyrus; Boerkoel, Cornelius F.; Bretherick, Karla L.; Brown, Lindsay; Chijiwa, Chieko; Clarke, Lorne; Couse, Madeline; Creighton, Susan; Watts-Dickens, Abby; Gibson, William T.; Gill, Harinder; Tarailo‐Graovac, Maja; Hamilton, Sara; Heran, Harindar; Horváth, Gabriella; Huang, Lijia; Hulait, Gurdip K.; Koehn, D.; Lee, Hyun Kyung; Sm, Lewis; Lopez, Elena; Louie, Kristal; Niederhoffer, Karen Y.; Matthews, Allison; Meagher, Kirsten; Peng, Junran J.; Patel, Millan S.; Race, Simone; Richmond, Phillip A.; Rupps, Rosemarie; Salvarinova, Ramona; Seath, Kimberly; Selby, Kathryn; Steinraths, Michelle; Stöckler, Sylvia; Tang, Kaoru; Tyson, Christine; Allen, Margot Van; Wasserman, Wyeth W.; Mwenifumbo, Jill; Friedman, Jan M.

doi:10.1016/j.xhgg.2022.100108

Cited by 15 publications

(24 citation statements)

References 55 publications

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“…All affected siblings received diagnoses by genome‐wide sequencing through the CAUSES study for medically complex disorders. The majority of probands who received diagnoses through CAUSES had autosomal dominant disorders however the cohort also included individuals with autosomal recessive and X‐linked recessive disorders (Elliott et al, 2022). Specific diagnoses of affected siblings in the current study are omitted to protect confidentiality; however, all had a rare genetic syndrome associated with intellectual disability.…”

Section: Resultsmentioning

confidence: 99%

The experiences of adolescent siblings of children with rare genetic conditions: “It's made me who I am”

Heaton

Wainstein

Elliott

et al. 2022

Journal of Genetic Counseling

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Childhood genetic conditions impact not only the child who is diagnosed but also the day-to-day lives of all members of a family. However, our understanding of the perspectives and needs of unaffected adolescents in families affected by rare genetic conditions is limited. To address this gap, we conducted semi-structured interviews with 10 participants aged 14-20 years, all of whom had a sibling with a rare genetic condition. An interpretive description approach was used to develop a framework that described how participants' experiences of having a sibling with a rare genetic condition shaped the formation of their identity. This experience influenced identity formation both directly, and indirectly through four other phenomena: (1) normalization, of both their own experiences and their siblings' differences; (2) knowledge seeking, regarding their sibling's condition and what uncertainties remained; (3) caretaking, which limited some opportunities and was associated with uncertainty around the future; and (4) social experience, including their relationship with their affected sibling, with their peers, and with the rest of their family participants felt that they were isolated and lacked appropriate supports. The results of this study can help to inform a family-centered approach to genetic counseling and highlight the importance of tailored supports for this population.

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Section: Resultsmentioning

confidence: 99%

The experiences of adolescent siblings of children with rare genetic conditions: “It's made me who I am”

Heaton

Wainstein

Elliott

et al. 2022

Journal of Genetic Counseling

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“…When testing is not available clinically, patients may opt to participate in research studies in order to obtain testing. The CAUSES Study, a translational research program, enrolled 500 families (531 children) from 2015–2018, providing trio‐based genome‐wide sequencing for BC pediatric patients suspected of having a genetic disorder 40 . The patients enrolled in the CAUSES Study would not have been captured in this analysis.…”

Section: Discussionmentioning

confidence: 99%

“…translational research program, enrolled 500 families (531 children) from 2015-2018, providing trio-based genome-wide sequencing for BC pediatric patients suspected of having a genetic disorder. 40 The patients enrolled in the CAUSES Study would not have been captured in this analysis.…”

Section: Conflict Of Interestmentioning

confidence: 99%

Evaluation of out‐of‐pocket pay genetic testing in a publicly funded healthcare system

et al. 2023

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When genetic tests are not funded publicly, out-of-pocket (OOP) pay options may be discussed with patients. We evaluated trends in genetic testing and OOP pay for two publicly funded British Columbia clinical programs serving >12 000 patients/year (The Hereditary Cancer Program [HCP] and Provincial Medical Genetics Program [PMGP]) between 2015-2019. Linear and regression models were used to explore the association of OOP pay with patient demographic variables at HCP. An interrupted time series and linear and logistic regression models were used on PMGP data to examine the effect of a change in the funding body. The total number of tests completed through PMGP, and HCP increased by 260% and 320%, respectively.OOP pay increased at HCP by 730%. The mean annual income of patients who paid OOP at HCP was ≥$3500 higher than in the group with funded testing (p < 0.0001).The likelihood of OOP pay increased at PMGP before the funding body change (OR per month: 1.07; 95% CI: 1.04, 1.10); while this likelihood had an immediate 87% drop when the change occurred (OR: 0.13; 95% CI: 0.06, 0.32). Patients with higher incomes are more likely to pay OOP. Financial barriers can create disparities in clinical outcomes. Funding decisions have a significant impact on rate of OOP pay.

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“…One patient was enrolled in the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) 5902 genetic research protocol (NCT00323167) and one in both the Care4Rare Canada whole exome sequencing protocol (https://www.care4rare.ca/) as well as the Silent Genomes Precision Diagnosis sequencing protocol (https://www.bcchr.ca/silentgenomes-project), performing research targeted Sanger sequencing, multigene panels whole exome sequencing or whole genome sequencing, using similar methods to those previously described. [11][12][13][14] Nasal nitric oxide testing was performed per standardized protocol, as previously described, 15 for patients seen at the MUHC or HSC.…”

Section: Methodsmentioning

confidence: 99%

First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit

Hunter-Schouela

Geraghty

Hegele

et al. 2023

Pediatric Pulmonology

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Background Primary ciliary dyskinesia (PCD) is typically an autosomal recessive disease characterized by recurrent infections of the lower respiratory tract, frequent and severe otitis media, chronic rhinosinusitis, neonatal respiratory distress, and organ laterality defects. While severe lower respiratory tract infections and bronchiectasis are common in Inuit, PCD has not been recognized in this population. Methods We report a case series of seven Inuit patients with PCD identified by genetic testing in three Canadian PCD centers. Results Patients ranged from 4 to 59 years of age (at time of last evaluation) and originated in the Qikiqtaaluk region (Baffin Island, n = 5), Nunavut, or Nunavik (northern Quebec, n = 2), Canada. They had typical features of PCD, including neonatal respiratory distress (five patients), situs inversus totalis (four patients), bronchiectasis (four patients), chronic atelectasis (six patients), and chronic otitis media (six patients). Most had chronic rhinitis. Genetic evaluation demonstrated that all had homozygous pathogenic variants in DNAH11 at NM_001277115.1:c.4095+2C>A. Conclusions The discovery of this homozygous DNAH11 variant in widely disparate parts of the Nunangat (Inuit homelands) suggests this is a founder mutation that may be widespread in Inuit. Thus, PCD may be an important cause of chronic lung, sinus, and middle ear disease in this population. Inuit with chronic lung disease, including bronchiectasis or laterality defects, should undergo genetic testing for PCD. Consideration of including PCD genetic analysis in routine newborn screening should be considered in Inuit regions.

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Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study

Cited by 15 publications

References 55 publications

The experiences of adolescent siblings of children with rare genetic conditions: “It's made me who I am”

The experiences of adolescent siblings of children with rare genetic conditions: “It's made me who I am”

Evaluation of out‐of‐pocket pay genetic testing in a publicly funded healthcare system

First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit

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