Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

Balci, Tugce B.; Hartley, Taila; Xi, Yanwei; Dyment, David A.; Beaulieu, Chandree L.; Bernier, François P.; Dupuis, Lucie; Horvath, Gabriella; Mendoza-Londoño, Roberto; Prasad, Chitra; Richer, Julie; Yang, Xunzhe; Armour, Christine M.; Bareke, Eric; Fernandez, Bridget A.; McMillan, Hugh J.; Lamont, Ryan E.; Majewski, Jacek; Parboosingh, Jillian S.; Prasad, Asuri N.; Rupar, C. Anthony; Schwartzentruber, Jeremy; Smith, Amanda; Tétreault, Martine; Innes, A. Micheil; Boycott, Kym M.

doi:10.1111/cge.12987

Cited by 98 publications

(85 citation statements)

References 32 publications

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“…The very poor genotype-phenotype correlation may be due to the interaction of additional genetic factors that may explain the observation of patients with HSP7 phenotypes associated with single heterozygous mutations S anchez-Ferrero et al, 2013). There is precedent for the interaction of different Mendelian disease genes causing unique phenotypes (Balci et al, 2017;Posey et al, 2017), and detailed study of such situations can produce novel mechanistic insights (Lee et al, 2018;Niu et al, 2018). Given the extensive unexplained heterogeneity in HSP, particularly in SPG7-and SPAST-related disease, these conditions would appear to be the best candidates for study, to identify novel modifier mechanisms.…”

Section: Discussionmentioning

confidence: 99%

High diagnostic yield and novel variants in very late-onset spasticity

Almomen

Martens

Quadir

et al. 2019

Journal of Neurogenetics

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Hereditary spastic paraplegias (HSPs) are a diverse group of genetic conditions with variable severity and onset age. From a neurogenetic clinic, we identified 14 patients with very late-onset HSP, with symptoms starting after the age of 35. In this cohort, sequencing of known genetic causes was performed using clinically available HSP sequencing panels. We identified 4 patients with mutations in SPG7 and 3 patients with SPAST mutations, representing 50% of the cohort and indicating a very high diagnostic yield. In the SPG7 group, we identified novel variants in two patients. We have also identified two novel mutations in the SPAST group. We present sequencing data from cDNA and RT-qPCR to support the pathogenicity of these variants, and provide observations regarding the poor genotypephenotype correlation in these conditions that should be the subject of future study. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

High diagnostic yield and novel variants in very late-onset spasticity

Almomen

Martens

Quadir

et al. 2019

Journal of Neurogenetics

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“…Large cohort studies of families undergoing whole exome sequencing have found that co-occurring genetic syndromes have occurred in 4.3% of their solved cases and 1% of the total WES cohort (Balci et al, 2017; Posey et al, 2017). While the majority of reported co-occurring genetic diagnoses with Turner syndrome are individual case reports, the percentage of dual diagnosis in the MGH Turner syndrome clinic was 1%.…”

Section: Discussionmentioning

confidence: 99%

Dual diagnoses in 152 patients with Turner syndrome: Knowledge of the second condition may lead to modification of treatment and/or surveillance

Jones

McNamara

Longoni

et al. 2018

American J of Med Genetics Pt A

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Turner syndrome is a sex chromosome abnormality in which a female has a single X chromosome or structurally deficient second sex chromosome. The phenotypic spectrum is broad, and atypical features prompt discussion of whether the known features of Turner syndrome should be further expanded. With the advent of clinical whole exome sequencing, there has been increased realization that some patients with genetic disorders carry a second genetic disorder, leading us to hypothesize that a “dual diagnosis” may be more common than suspected for Turner syndrome. We report five new patients with Turner syndrome and a co-occurring genetic disorder including one patient with Li-Fraumeni syndrome, Li-Fraumeni and Noonan syndrome, mosaic trisomy 8, pathogenic variant in RERE, and blepharophimosis-ptosis-epicanthanus inversus syndrome. We also undertook an extensive literature review of 147 reports of patients with Turner syndrome and a second genetic condition. A total of 47 patients (31%) had trisomy 21, followed by 36 patients (24%) had one of 11 X-linked disorders. Notably, 80% of the 147 reported patients with a dual diagnosis had mosaicism for Turner syndrome, approximately twice the frequency in the general Turner syndrome population. This article demonstrates the potential for co-occurring syndromes in patients with Turner syndrome, prompting us to recommend a search for an additional genetic disorder in Turner patients with unusual features. Knowledge of the second condition may lead to modification of treatment and/or surveillance. We anticipate that increased awareness and improved diagnostic technologies will lead to the identification of more cases of Turner syndrome with a co-occurring genetic syndrome.

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“…If these were independent events, the probability of co-occurrence is around 1/40 million, or under 10 similar cases in the United States. The co-occurrence of multiple genetic syndromes (so-called “blended” phenotypes) has been reported in ~4% of individuals referred for clinical genetic testing (13, 14), particularly in people like EF with multisystem disease.…”

Section: Discussionmentioning

confidence: 99%

Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington’s Disease

Farrell

Lichtenstein

Crowley

et al. 2018

AJP

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Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

Abstract: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

Cited by 98 publications

References 32 publications

High diagnostic yield and novel variants in very late-onset spasticity

High diagnostic yield and novel variants in very late-onset spasticity

Dual diagnoses in 152 patients with Turner syndrome: Knowledge of the second condition may lead to modification of treatment and/or surveillance

Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington’s Disease

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