Is one diagnosis the whole story? patients with double diagnoses

Kurolap, Alina; Orenstein, Naama; Kedar, Inbal; Hubshman, Monika Weisz; Tiosano, Dov; Mory, Adi; Levi, Zohar; Marom, Daphna; Cohen, Lior; Ekhilevich, Nina; Douglas, Jessica; Nowak, C.; Tan, Wen‐Hann; Baris, Hagit N.

doi:10.1002/ajmg.a.37799

Cited by 23 publications

(19 citation statements)

References 32 publications

(34 reference statements)

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“…Other case studies have revealed at least 3 patients (2 male, 1 female) with a small deletion of a chromosome harbouring genes implicated in hereditary nonpolyposis colorectal cancer (2p, 3p, 7p) who also had IDs and developed colon cancer, 2 of them early in life [41][42][43]. For example, a male patient with a mutation in the PMS2 gene was diagnosed with a rectal carcinoma aged 14 years [44], whilst a man with mild to moderate ID due to Williams syndrome and Lynch syndrome (which increases the risk for colon neoplasia) developed a colorectal cancer aged 37 years [45]. In a Danish cohort of 597 women with Turner syndrome, those who presented with mild IDs were found to be at a higher risk of colon cancer compared to women in the general population [46].…”

Section: Genetic Conditionsmentioning

confidence: 99%

Colorectal Cancer in People with Intellectual Disabilities

Willis

Samalin

Satge³

2018

Oncology

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People with intellectual disabilities (PWIDs) are now living longer; thus, the incidence of cancer within this population is increasing. Available data indicate an excess of digestive tract cancers in PWIDs, but colorectal cancer has rarely been specifically studied and has not been extensively reviewed. This is despite risk factors such as being overweight, obesity, and lack of exercise being more frequent in PWIDs. In this article, we examine the literature on the frequency, screening, and treatment of colorectal cancer in PWIDs by as sessing 4 databases, Medline, EBSCO-CINHL, ASSIA, and PsychLIT, from 1970 to February 2017. Findings indicate that the frequency trends slightly higher than that found in the general population. Screening presents a unique opportunity to discover early colorectal cancer, but is underused in PWIDs compared to the general population. Furthermore, the clinical presentation is frequently masked, particularly by challenging behaviours, and colorectal cancer is therefore often diagnosed late, making treatment difficult due to the advanced stage of these tumours. To improve the care of PWIDs, we need more resources to support them and their caregivers, and to increase awareness of the risk factors and signs and symptoms of colorectal cancer.

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Section: Genetic Conditionsmentioning

confidence: 99%

Colorectal Cancer in People with Intellectual Disabilities

Willis

Samalin

Satge³

2018

Oncology

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“…The affected individuals in Families II and III do not carry mutations in CYP17A1 or have CAH, suggesting the presence of two independent and unrelated conditions in Family I. The co-occurrence of multiple monogenic disorders is not uncommon among this highly consanguineous population (Kurolap et al, 2016).…”

Section: Resultsmentioning

confidence: 84%

Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

Tiosano

Feldman

Chen

et al. 2018

Preprint

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PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity.Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

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“…In a previous publication we reported that founder mutations and consanguinity are two factors that should raise the index of suspicion for a double diagnosis. 10 These possible diagnostic errors emphasize the importance of a non-biased analysis provided by WES.…”

Section: Discussionmentioning

confidence: 99%

Rare Disease Diagnostics: A Single-center Experience and Lessons Learnt

Weiss¹,

Kurolap²,

Paperna³

et al. 2018

Rambam Maimonides Med J

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ObjectiveThe growing availability of next-generation sequencing technologies has revolutionized medical genetics, facilitating discovery of causative genes in numerous Mendelian disorders. Nevertheless, there are still many undiagnosed cases. We report the experience of the Genetics Institute at Rambam Health Care Campus in rare disease diagnostics using whole-exome sequencing (WES).MethodsPhenotypic characterization of patients was done in close collaboration with referring physicians. We utilized WES analysis for diagnosing families suspected for rare genetic disorders. Bioinformatic analysis was performed in-house using the Genoox analysis platform.ResultsBetween the years 2014 and 2017, we studied 34 families. Neurological manifestations were the most common reason for referral (38%), and 55% of families were consanguineous. A definite diagnosis was reached in 21 cases (62%). Four cases (19%) were diagnosed with variants in novel genes. In addition, six families (18%) had strong candidate novel gene discoveries still under investigation. Therefore, the true diagnosis rate is probably even higher. Some of the diagnoses had a significant impact such as alerting the patient management and providing a tailored treatment.ConclusionsAn accurate molecular diagnosis can set the stage for improved patient care and provides an opportunity to study disease mechanisms, which may lead to development of tailored treatments. Data from our genetic research program demonstrate high diagnostic and novel disease-associated or causative gene discovery rates. This is likely related to the unique genetic architecture of the population in Northern Israel as well as to our strategy for case selection and the close collaboration between analysts, geneticists, and clinicians, all working in the same hospital.

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Is one diagnosis the whole story? patients with double diagnoses

Cited by 23 publications

References 32 publications

Colorectal Cancer in People with Intellectual Disabilities

Colorectal Cancer in People with Intellectual Disabilities

Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

Rare Disease Diagnostics: A Single-center Experience and Lessons Learnt

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