Genetic Counseling and NGS Screening for Recessive LGMD2A Families.

Giulia Campoli,Raffaella Cascella,Rosaria Maria Galota,Julia Mela,Stefania Zampatti,Claudia Strafella,Giulietta Minozzi,Emiliano Giardina,Serenella Servidei,Valerio Caputo,Cristina Sancricca

doi:10.3390/ht9020013

Abstract

Genetic counseling applied to limb–girdle muscular dystrophies (LGMDs) can be very challenging due to their clinical and genetic heterogeneity and the availability of different molecular assays. Genetic counseling should therefore be addressed to select the most suitable approach to increase the diagnostic rate and provide an accurate estimation of recurrence risk. This is particularly true for families with a positive history for recessive LGMD, in which the presence of a known pathogenetic mutation segregating within the family may not be enough to exclude the risk of having affected children without exploring the genetic background of phenotypically unaffected partners. In this work, we presented a family with a positive history for LGMD2A (OMIM #253600, also known as calpainopathy) characterized by compound heterozygosity for two CAPN3 mutations. The genetic specialist suggested the segregation analysis of both mutations within the family as a first-level analysis. Sequentially, next-generation sequencing (NGS) analysis was performed in the partners of healthy carriers to provide an accurate recurrence/reproductive risk estimation considering the genetic background of the couple. Finally, this work highlighted the importance of providing a genetic counseling/testing service even in unaffected individuals with a carrier partner. This approach can support genetic counselors in estimating the reproductive/recurrence risk and eventually, suggesting prenatal testing, early diagnosis or other medical surveillance strategies.

Highlights

An adequate management of genetic disorders in terms of clinical/molecular diagnosis, prediction of prognosis and possible complications and the estimation of a reliable recurrence risk within a family is essentially based on an accurate and comprehensive genetic counseling
Pedigree analysis remains crucial in genetic counseling, it is normally complemented with an extensive molecular analysis in order to provide the molecular diagnosis of the disease and an accurate estimate of the recurrence/reproductive risk and an adequate counseling to the patients
We proposed a workflow for estimating an accurate recurrence risk and providing an adequate pre- and post-test genetic counseling service to families presenting a clinical history for recessive disorders because of the presence of one or more pathogenic mutations segregating in the family members

Summary

Introduction

An adequate management of genetic disorders in terms of clinical/molecular diagnosis, prediction of prognosis and possible complications and the estimation of a reliable recurrence risk within a family is essentially based on an accurate and comprehensive genetic counseling. We proposed a workflow for estimating an accurate recurrence risk and providing an adequate pre- and post-test genetic counseling service to families presenting a clinical history for recessive disorders because of the presence of one or more pathogenic mutations segregating in the family members.

Results

Conclusion