An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Molecular Analyses
2.3. Bioinformatics
2.4. Variant Pathogenicity Evaluation
3. Results
3.1. Diagnostic Efficiency in Each Phenotypic Group
3.2. Atypical Phenotype-Genotype Associations
3.2.1. Expanded Phenotype-Genotype Associations
3.2.2. Mild Phenotypes
3.2.3. Recently Identified Phenotype-Genotype Associations
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient Sex, Age/ Age at Onset | Clinical Features | CK | Muscle Biopsy | Muscle MRI | Family History | Genetic Testing |
---|---|---|---|---|---|---|
I298 M, 38y/ neonatal | Neonatal hypotonia Scoliosis Progressive myopathy with contractures Early-onset cardiomyopathy Restrictive respiratory syndrome | N | Type I fiber predominance. Cytoplasmic bodies | ND | Sporadic | c.3557C>T; p.(Ala1186Val) FLNC NM_001458.4 Missense de novo variant Absent in Exac and gnomAD |
I111 F, 4y/ 1y | Pierre Robin sequence (micrognathia, glossoptosis, and cleft palate), scoliosis Feeding difficulties Severe restrictive cardiomyopathy Mild proximal and axial weakness | N | Type I fiber atrophy | Normal | Sporadic | c.4927+2T>A FLNC de novo splicing variant HSF, MaxEnt: -100% Absent in Exac and gnomAD |
I192 M, 20y/ 20y | Asymptomatic CK elevation Strictly normal neurological examination | x20 | Some necrotic fibers Absence of rods | Normal | Sporadic | c.889G>A; p.(Ala297Thr) ACTA1 NM_001100.3 de novo missense variant. Absent in Exac and gnomAD |
I14 F, 75y/ 60y | Slowly progressive axial weakness with camptocormia Mild lower limb proximal weakness No ptosis, no dysphagia | N | Abnormal myofibrillar network Rimmed and not rimmed vacuoles | Paravertebral VL, AB, AM, SM, GM, SO | Sporadic | c.30_31insGCA; p.(Ala11dup) PAPBN1 NM_004643.3 |
I303 F, 30y/ neonatal | Neonatal hypotonia with feeding difficulties and respiratory insufficiency Progressive improvement Last follow-up visit: mild axial and proximal weakness Gowers + Distal hyperlaxity Worsening with fever | N | Non-specific myopathic pattern with type 1 fiber predominance and mild myofibrillar disorganization | Upper and lower limbs atrophy. No fat tissue replacement | AR (deceased affected brother) | c.2970G>A; p.(Trp990*) CACNA1S c.5104C>T; p.(Arg1702*) CACNA1S NM_000069.2 |
I164 M, 21y/ neonatal | Neonatal hypotonia, feeding difficulties, respiratory insufficiency Last follow-up visit: tongue deviation, mild bilateral facial paresis, mild bilateral scapula alata, proximal lower limb weakness, distal hyperlaxity | N | Non-specific myopathic pattern with type 1 fiber predominance | Tongue GMax | Pauci symptomatic father carries the variant | c.2447T>G; p.(Leu816Arg) CACNA1S Missense variant predicted to be deleterious Absent in Exac and gnomAD |
I142 F, 40y/ 35y | Bilateral calf and left tibialis anterior atrophy | N | Excessive internal nuclei. Minicores with NADH technique | Bilateral GM and left TA | AD | del <11-18> exons TTN NM_001267550.1 |
I26 M, 14y/ 3y | Very mild proximal weakness Mild facial paresis Moderate restrictive respiratory syndrome | N | Excessive internal nuclei resembling centronuclear myopathy. Minicores revealed by NADH staining | Normal | Adopted child | c.51437-4_51444del TTN c.26503A>T; p.(Lys8835*) TTN |
I47 F, 44y/ 4y | Proximal and axial weakness Wheelchair at the age of 17 Last follow-up visit: severe proximal and axial weakness, restrictive respiratory syndrome | N | Excessive internal nuclei resembling centronuclear myopathy. Minicores revealed by NADH staining | Bilateral SO and left TA | Sporadic | c.65575+2T>G TTN c.68029A>G; p.(Thr22677Ala) TTN Missense variant predicted to affect splicing |
I74, I73 F, 4y/ 3y | Mild proximal and axial weakness Facial paresis | x2 | Excessive internal nuclei Minicores in NADH staining. Abnormal western blot results: absence of the C-terminal part of TTN (anti-TTN M10-1 antibody); absence of calpain | N.D | Affected twin sister | c.106531G>C; p.(Ala35511Pro) TTN Missense variant predicted to affect splicing c.105036C>A; p.(Tyr35012*) TTN |
I76, I77 M, 54y F, 50y/ 35y | Isolated tibialis anterior weakness Recently the brother developed finger extensor and neck flexor weakness | N | Pathological fiber size variation. Excessive internal nuclei Absence of rods | Bilateral TA and GM in both patients | AR | c.8860delG p.(Ala2954Profs*8) NEB NM_001271208.1 c.21928T>C; p.(Ser7310Pro) NEB |
I112 M, 60y/ 57y | Isolated tibialis anterior weakness | N | Pathological fiber size variation. Absence of rods | Bilateral TA and left SO | Sporadic | c.21790G>C p.(Arg7264His) NEB c.194C>T p.(Pro65Leu) NEB |
I60 M, 61y/ 20y | Axial and proximal weakness Retrognathia, pectus excavatum Mild rigid spine Dilated cardiomyopathy | N | Excessive internal nuclei Minicore-like lesions, rods | Bilateral SM, BF, SO | Sporadic (Consang) | del <8-9> homozygous exons TRIP4 NM_016213.4 In-Frame deletion of exons 8 and 9 |
I172 F, 11y/ neonatal | Neonatal hypotonia Proximal and axial weakness in childhood. Gowers + Mild tibialis anterior weakness Scapula alata Facial paresis | N | Excessive internal nuclei | Bilateral GMax, AM, SM, BF, TA, SO, P | Sporadic | c.200A>G; p.(His67Arg) TNNT1 NM_003283.5 de novo missense variant Absent in Exac and gnomAD |
I152 M, 35y/ 20y | Lower limb-girdle muscular dystrophy | x20 | Non-specific dystrophic pattern | Bilateral VL, AM, AB, SM, ST, GM | AR Affected sister. Consang | c.6617C>T; p.(Thr2206Met) Homozygous RYR1 NM_000540.2 Missense variant |
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Juntas Morales, R.; Perrin, A.; Solé, G.; Lacourt, D.; Pegeot, H.; Walther-Louvier, U.; Cintas, P.; Cances, C.; Espil, C.; Theze, C.; et al. An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families. Genes 2021, 12, 1199. https://doi.org/10.3390/genes12081199
Juntas Morales R, Perrin A, Solé G, Lacourt D, Pegeot H, Walther-Louvier U, Cintas P, Cances C, Espil C, Theze C, et al. An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families. Genes. 2021; 12(8):1199. https://doi.org/10.3390/genes12081199
Chicago/Turabian StyleJuntas Morales, Raul, Aurélien Perrin, Guilhem Solé, Delphine Lacourt, Henri Pegeot, Ulrike Walther-Louvier, Pascal Cintas, Claude Cances, Caroline Espil, Corinne Theze, and et al. 2021. "An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families" Genes 12, no. 8: 1199. https://doi.org/10.3390/genes12081199
APA StyleJuntas Morales, R., Perrin, A., Solé, G., Lacourt, D., Pegeot, H., Walther-Louvier, U., Cintas, P., Cances, C., Espil, C., Theze, C., Zenagui, R., Yauy, K., Cosset, E., Renard, D., Rigau, V., Maues de Paula, A., Uro-Coste, E., Arne-Bes, M.-C., Martin Négrier, M.-L., ... Cossée, M. (2021). An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families. Genes, 12(8), 1199. https://doi.org/10.3390/genes12081199