Inferring parental gonadal mosaicism in <i>LMNA</i>‐associated muscular dystrophy by ultra‐deep next generation sequencing: A sensitive approach providing valuable information for genetic counseling

Maturo, Josefina Pérez; Vega, Patricia; Medina, Nancy; Salinas, Valeria; Pauni, Micaela; Agosta, Guillermo; Muntadas, Javier; Kauffman, Marcelo

doi:10.1002/ajmg.a.61135

Cited by 4 publications

(2 citation statements)

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“…Currently, arriving at a definitive diagnosis is a challenging and complex situation due to the constant increase in genetic knowledge. The growing role of mosaic variants in some entities such as epilepsies (de Lange et al, 2018), epileptic encephalopathies (Myers et al, 2018) and neuromuscular disorders (Perez Maturo et al, 2019) require the implementation of innovative sequencing and bioinformatic analysis methods for their detection and validation.…”

Section: Discussionmentioning

confidence: 99%

The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

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The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology. K E Y W O R D S diagnostic odyssey, mosaicism, targeted gene panel sequencing, variants of unknown significance, whole exome sequencing 1 | INTRODUCTION Neurogenetic diseases encompass a vast group of entities with marked genetic and phenotypic heterogeneity. Nowadays, the process of establishing a diagnosis for this subset of neurological conditions requires extensive clinical, radiological, and genetic evaluations, often becoming a "diagnostic odyssey" for the patient and the family (Carmichael, Tsipis, Windmueller, Mandel, & Estrella, 2015). Next Generation Sequencing (NGS) has become a widely used tool for obtaining genetic diagnosis in clinical medicine (Might &

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Section: Discussionmentioning

confidence: 99%

The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

Self Cite

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“…Makri et al ( 2009 ) presented a consanguineous family in which two children had early onset LMNA ‐related myopathy, most likely due to paternal germinal mosaicism. Maturo et al ( 2019 ) reported two sisters with heterozygous mutations in LMNA gene (c.1357C>T), presenting with LMNA ‐associated muscular dystrophy. A pedigree analysis was subsequently performed by using ultra‐deep sequencing (13,000×) and this successfully detected a low level of maternal mosaicism (3%).…”

Section: Discussionmentioning

confidence: 99%

Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

Xie

Luo

Zhong

et al. 2023

Molec Gen & Gen Med

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Background Emery–Dreifuss muscular dystrophy (EDMD2) is a rare form of muscular dystrophy that is inherited as an autosomal dominant trait. In some patients, it is inherited from parental mosaicism, and this increases the recurrence risk significantly. The presence of mosaicism is underestimated due to the limitations of genetic testing and the difficulty in obtaining samples. Methods A peripheral blood sample from a 9‐year‐old girl with EDMD2 was analyzed by enhanced whole exome sequencing (WES). Sanger sequencing in her unaffected parents and younger sister was performed for validation. In the mother, ultra‐deep sequencing and droplet digital PCR (ddPCR) in multiple samples (blood, urine, saliva, oral epithelium, and nail clippings) were performed in order to identify the suspected mosaicism of the variant. Results WES revealed a heterozygous mutation (LMNA, c.1622G>A) in the proband. Sanger sequencing of the mother suggested the presence of mosaicism. The ratio of mosaic mutation was confirmed in different samples by ultra‐deep sequencing and ddPCR (19.98%–28.61% and 17.94%–28.33%, respectively). This inferred that the mosaic mutation may have occurred early during embryonic development and that the mother had gonosomal mosaicism. Conclusion We described a case of EDMD2 caused by maternal gonosomal mosaicism which was confirmed by using ultra‐deep sequencing and ddPCR. This study illustrates the importance of a systematic and comprehensive screening of parental mosaicism with more sensitive approaches and the use of multiple tissue samples.

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Molecular Genetics and Prenatal Diagnosis

Milunsky

2021

Genetic Disorders and the Fetus

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Inferring parental gonadal mosaicism in LMNA‐associated muscular dystrophy by ultra‐deep next generation sequencing: A sensitive approach providing valuable information for genetic counseling

Cited by 4 publications

References 14 publications

The odyssey of complex neurogenetic disorders: From undetermined to positive

The odyssey of complex neurogenetic disorders: From undetermined to positive

Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

Molecular Genetics and Prenatal Diagnosis

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