Utility of next-generation sequencing in genetic testing and counseling of disorders involving the musculoskeletal system\u2014trends observed from a single genetic unit

Gayatri R Iyer,Vaishnavi Suresh,Subhadra Poornima,Akhilesh N Pujar,Keerthi Konda Juturu,Lekhangda Bhatnagar,Srinka Arora,Prashant R Utage,Aruna Priya Kamireddy,Sarah Bailur,Roshan Kumar,Qurratulain Hasan

doi:10.1186/s13018-022-02969-x

Gayatri R Iyer, Vaishnavi Suresh + Show 10 more

Open Access

https://doi.org/10.1186/s13018-022-02969-x

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Abstract

BackgroundDisorders involving the musculoskeletal system are often identified with short stature and a range of orthopedic problems. The clinical and genetic heterogeneity of these diseases along with several characteristic overlaps makes definitive diagnosis difficult for clinicians. Hence, using molecular testing in addition to conventional tests becomes essential for appropriate diagnosis and management.MethodsComprehensive clinical examination, detailed pretest and posttest counseling, molecular diagnosis with next-generation sequencing (NGS), genotype–phenotype correlation and Sanger sequencing for targeted variant analysis.ResultsThis manuscript reports a molecular spectrum of variants in 34 orthopedic cases referred to a single genetic unit attached to a tertiary care hospital. The diagnostic yield of NGS-based tests coupled with genetic counseling and segregation analysis was 79% which included 7 novel variants. In about 53% (i.e. 18/34 cases), molecular testing outcome was actionable since 8 of the 18 underwent prenatal diagnosis, as they were either in their early gestation or had planned a pregnancy subsequent to molecular testing, while ten cases were premaritally/prenatally counseled for the families to take informed decisions as they were in the reproductive age.ConclusionsThe report highlights the importance of NGS-based tests even in a low resource setting as it helps patients, families and healthcare providers in reducing the economic, social and emotional burden of these disorders.

Highlights

Disorders involving the musculoskeletal system (DMS) are generalized abnormalities of the muscle and skeletal system often marked by short stature and a spectrum of mobility and orthopedic problems [1]
What’s new? The article demonstrates utility of next-generation sequencing in Indian population and illustrates the importance in using the test for optimal benefits in clinical management, surveillance, prenatal diagnosis and eventually bringing down morbidity and mortality of musculoskeletal disorders
We evaluated the role of next-generation sequencing (NGS) in diagnosing patients with musculoskeletal abnormalities referred to the Genetics unit of a tertiary care hospital in South India with comprehensive pre- and posttest genetic counseling to help patients and their families in taking informed healthcare and reproductive decisions

Summary

Introduction

Disorders involving the musculoskeletal system (DMS) are generalized abnormalities of the muscle and skeletal system often marked by short stature and a spectrum of mobility and orthopedic problems [1]. DMS predominantly affects the muscle, cartilage or skeletal system and is associated with several genetic syndromes Patients with these disorders in India report either to pediatric, neurology or orthopedic departments with skeletal abnormalities, altered gait, short stature or joint pain. Type of inheritance can be deduced in some cases like autosomal dominant (AD), autosomal recessive (AR) or X-linked dominant (XD) and recessive forms (XR) depending on the location of the associated genes [6]. Confirmation for this again comes after molecular diagnosis. Using molecular testing in addition to conventional tests becomes essential for appropriate diagnosis and management

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