Counseling and prenatal diagnosis in facioscapulohumeral muscular dystrophy: A retrospective study on a 13‐year multidisciplinary approach

Abstract

Background and Aims: This is the first national population-based report about prenatal diagnosis for families with a history of facioscapulohumeral muscular dystrophy (FSHD), a complex hereditary disease. The incomplete disease penetrance and the phenotypic heterogeneity observed in carriers of D4Z4 alleles of reduced size, the FSHD molecular hallmark, make the estimate of genetic risk problematic. Methods:We considered all requests of preconception counseling and prenatal diagnosis received between January 2008 and December 2020 by the genetic counseling service associated with the Italian National Registry for FSHD (INRF).A multidisciplinary team managed the clinical and molecular data of each family.Results: Between 2008 and 2020, 60 couples required preconception counseling (PC) for FSHD. In 52 couples was observed at least one partner carried a D4Z4 reduced allele (DRA). Out of these 52 couples, 47 had a follow-up visit routine yearly. Out of these 47, 26 (55.3%) couples had children: eight asked for prenatal diagnosis (PND), two had assisted reproduction by heterologous in vitro fertilization (IVF), and 16 did not require further assistance. Regarding PND, 50 prenatal analyses were performed for 36 couples. The test resulted positive in 27 pregnancies, 12 (44.4%) were terminated, and 15 (55.6%) were carried to term. Conclusion:The different choices made by the couples show the importance of an integrated approach to support genetic counseling for FSHD. These results remark the relevance of the clinical and molecular investigation of the extended family, preferably before conception.

De novo variants and recombination at 4q35: Hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy

“…These conditions make genetic counseling challenging and the decision‐making process arduous for couples 6 . At present beside prenatal diagnosis (PND), preimplantation genetic testing for monogenic disorders (PGT‐M) is also offered.…”

“…These conditions make genetic counseling challenging and the decision‐making process arduous for couples. 6 At present beside prenatal diagnosis (PND), preimplantation genetic testing for monogenic disorders (PGT‐M) is also offered. In the case of FSHD PGT‐M is based on the indirect analysis of D4Z4 by PCR amplification of nearby polymorphic markers ( https://www.fshdsociety.org/diagnosis/genetic-testing/ ).…”

“…In the case of FSHD PGT‐M is based on the indirect analysis of D4Z4 by PCR amplification of nearby polymorphic markers ( https://www.fshdsociety.org/diagnosis/genetic-testing/ ). This is because the methodology routinely performed for FSHD PND requires large amounts of high molecular weight genomic DNA from chorionic villi or amniocytes, 6 instead very low quantities of genomic material are required for PGT‐M. 7 …”

The FSHD jigsaw: are we placing the tiles in the right position?

“…In itself, the D4Z4 array structure impedes direct testing in preimplantation genetic diagnosis [50], and the highly recombinogenic nature of the 4q and 10q subtelomeres obstacles the use of alternative markers for PGD [51]. More recently, molecular combing [52–54] and optical mapping techniques (OGM) [55,56] have emerged to estimate the size of the array.…”

First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

“…In China, the majority of FSHD1 families express the desire for prenatal diagnosis of FSHD1, aiming to prepare in advance for the birth of affected children. Considering the complex structural variations in FSHD1 and the 99% homology of the 4q35 and 10q26 regions, molecular diagnosis of FSHD1 is a formidable challenge, and prenatal diagnosis even more so (Di Feo et al, 2022; Upadhyaya et al, 1999). Current methods for prenatal diagnosis of FSHD1 include Karyomapping (Zheng et al, 2020) and Bionano single‐molecule optical mapping (BOM) (Dai et al, 2020; Stence et al, 2021).…”