Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility

Nadia Waheed,Huma Cheema,Arndt Rolfs,Volha Skrahina,Jordi Perez-Lopez,Najim Ameziane,Peter Bauer,Salem Alawbathani,Maria Eugenia Rocha,Omid Paknia,Catarina Pereira,Claudia Cozma,Muhammad Nadeem Anjum,Aida M. Bertoli-Avella,Christian Beetz,Anjum Saeed,Irene Rosita Pia Patric,Marina Hovakimyan

doi:10.1038/s41525-020-00150-z

Nadia Waheed, Huma Cheema

Open Access

https://doi.org/10.1038/s41525-020-00150-z

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Abstract

We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and to asses diagnostic yield and clinical impact in patients with suspected genetic diseases. Local physicians ascertained pediatric patients who had no previous access to genetic testing. More than 1586 genetic tests were performed in 1019 individuals (349 index cases, 670 relatives). Most frequently performed tests were exome/genome sequencing (ES/GS, 284/78 index cases) and specific gene panels (55 index cases). In 61.3% of the patients (n = 214) a genetic diagnosis was established based on pathogenic and likely pathogenic variants. Diagnostic yield was higher in consanguineous families (60.1 vs. 39.5%). In 27 patients, genetic diagnosis relied on additional biochemical testing, allowing rapid assessment of the functional effect of the variants. Remarkably, the genetic diagnosis had a direct impact on clinical management. Most relevant consequences were therapy related such as initiation of the appropriated treatment in a timely manner in 51.9% of the patients (n = 111). Finally, we report 12 candidate genes among 66 cases with no genetic diagnosis. Importantly, three of these genes were validated as ‘diagnostic’ genes given the strong evidence supporting causality derived from our data repository (CAP2-dilated cardiomyopathy, ITFG2-intellectual disability and USP53-liver cholestasis). The high diagnostic yield, clinical impact, and research findings demonstrate the utility of genomic testing, especially when used as first-line genetic test. For patients with suspected genetic diseases from resource-limited regions, ES can be considered as the test of choice to achieve genetic diagnosis.

Highlights

Genetic diseases are often severely disabling and have detrimental impact on patients’ physical and cognitive abilities
295 families reported parental consanguinity, which was expected given the geographical origin of the patients, where intra-familiar marriages are more commonplace
We have shown the excellent diagnostic value of ES/ GS as first-line testing in patients with suspected genetic diseases

Summary

Introduction

Genetic diseases are often severely disabling and have detrimental impact on patients’ physical and cognitive abilities. Such lifelong impairments have a considerable impact on affected families[1]. An accurate diagnosis will guide clinical decisions, allowing for personalized medical management, monitoring and more accurate prognosis. It is of maximum relevance in cases with treatable genetic diseases, where establishing a specific treatment program can make a major difference in outcome[2,3,4,5]. For the families, establishing a diagnosis allows for genetic counseling, including information on recurrence risk, and facilitates family planning and reproductive choices. An accurate diagnosis advances access to information and assistance from patient support groups as well as access to the education, health, and social care systems, forming the basis for research into new therapies[6]

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