The novel pathogenic variant in the LMNA gene in a four-generation family with sudden deaths and cardiomyopathy: Utility of molecular autopsy

Abstract Background Classical heterozygous pathogenic variants of the lamin A/C (LMNA) gene cause familial partial lipodystrophy type 2 (FPLD2). However, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants, and a few patients have been associated with generalized fat loss. Clinical Case Here, we report a patient with lamin A specific pathogenic variant at exon 11 LMNA p.R582H present in homozygous state. Fat distribution was compared radiographically to a heterozygote LMNA p.R582H patient from another pedigree, female healthy control, a series of adult female subjects with congenital generalized lipodystrophy type 1 (CGL1, n = 9) and typical FPLD2 (n = 8). The whole body MRI of the index case confirmed near-total loss of subcutaneous adipose tissue with well-preserved fat in the retroorbital area, palms and soles, mons pubis, and external genital region. This pattern resembled the fat loss pattern observed in CGL1 with only one difference: strikingly more fat was observed around mons pubis and the genital region. Also, homozygous p.R582H LMNA variant was associated with lower leptin level and earlier onset of metabolic abnormalities compared to heterozygous p.R582H variant and typical FPLD2 cases. On the other hand, heterozygous LMNA p.R582H variant was associated with partial fat loss which was similar to typical FPLD2 but less severe than the patients with the hot-spot variants at position 482. Conclusions Our observations and radiological comparisons demonstrate a gene dosage effect of LMNA variants on the severity of fat loss and add to the body of evidence that there may be complex genotype-phenotype relationships in this interesting disease known as FPLD2. Although the pathological basis for fat loss is not well understood in patients harboring pathogenic variants in the LMNA gene, our observation suggests that genetic factors modulate the extent of fat loss in LMNA associated lipodystrophy.

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Feministic Analysis of Arundhati Roy's Postmodern Indian Fiction: The God of Small Things

GATR Global Journal of Business Social Sciences Review - GATR Global Journal of Business and Social Science Review (GJBSSR) Vol.7(1) Jan-Mar 2019 ◽

10.35609/gjbssr.2017.5.3(17) ◽

2017 ◽

Vol 5 (3) ◽

pp. 159-164

Author(s):

A. Hariharasudan ◽

S. Robert Gnanamony

Keyword(s):

Gender Bias ◽

Jel Classification ◽

Social Structures ◽

The Novel ◽

Female Characters ◽

Arundhati Roy ◽

Generation Family ◽

Paper Review ◽

The Difference ◽

Small Things

Objective - The aim of the research is to identify the feminist strains in the postmodern Indian Fiction The God of Small Things (TGST). The researcher has planned to investigate the text systematically for seeking feministic values. Methodology/Technique - The study reviews previous literature. Findings - Gender bias and feminism are relevant themes explored by postmodernists. Arundhati Roy portrays the predicament of women through her female characters belonging to three generations in this novel. In the novel, a sense of antagonism and division also infuse the difference senses of identity among the different generation of women. It also generates a line of the clash between the older and the younger generation. Family and political customs play a key role in disadvantaging women. Social constrains are so built up as to sanctify the persecution of women. This is because, in most of the civilizations, social structures are basically patriarchal. Arundhati's novel challenges this position, though her avowed feminist stance. Novelty - Women across the globe worldwide, nationwide, regionally and may be capable of holding the influential note of feminism and being capable of deconstructing a constructive implication of their own femaleness and womanhood after reading this paper. Type of Paper: Review Keywords: Feminism; Gender Bias; Patriarchal; Postmodernism; Downtrodden. JEL Classification: B54, H83.

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Identification of a novel pathogenic variant in the MYH3 gene in a five‐generation family with CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A)

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.1440 ◽

2020 ◽

Vol 8 (10) ◽

Author(s):

Jing Zhang ◽

Wen‐Qi Chen ◽

Si‐Wen Wang ◽

Shao‐Xiong Wang ◽

Mei Yu ◽

...

Keyword(s):

Pathogenic Variant ◽

Generation Family ◽

Myh3 Gene

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2287 ECG and echo characteristics in familial partial lipodystrophy: The impact of Lamin A variants

Journal of Clinical and Translational Science ◽

10.1017/cts.2018.164 ◽

2018 ◽

Vol 2 (S1) ◽

pp. 41-42

Author(s):

Abdelwahab J. Eldin ◽

Rasimcan Meral ◽

Adam H. Neidert ◽

Diana Rus ◽

Rita Hench ◽

...

Keyword(s):

Pathogenic Variant ◽

Lamin A ◽

Lmna Gene ◽

Partial Lipodystrophy ◽

Severe Insulin Resistance ◽

Inherited Cardiomyopathy ◽

Increased Risk ◽

Low Hdl ◽

Familial Partial Lipodystrophy ◽

The Impact

OBJECTIVES/SPECIFIC AIMS: Familial partial lipodystrophy (FPLD) is an inherited, rare syndrome characterized by selective absence of adipose tissue from extremities which is associated with severe insulin resistance, and metabolic dyslipidemia (with hypertriglyceridemia, and low HDL) Typically, 30%–50% of patients with FPLD demonstrate a pathogenic variant in Lamin A (LMNA) gene that is associated with inherited cardiomyopathy and arrhythmia syndromes. We inquired the prevalence of having abnormal ECGs and echocardiograms in FPLD and whether there is a difference in evaluated parameters with respect to genotype. METHODS/STUDY POPULATION: We conducted a retrospective review of an established a cohort of 58 patients (age range: 12–71, M/F 8/50) with FPLD. Demographic characteristics, genotype, fasting triglyceride, hemoglobin A1c, LDL, and HDL levels were collected; ECGs and echocardiograms were also interrogated. RESULTS/ANTICIPATED RESULTS: Out of 58 patients, 22 (38 %) displayed a pathogenic variant in the LMNA gene. In total, 71% of patients (41/58) had an abnormal ECG and echocardiogram; 40% (23/58) of the patients displayed an arrhythmia on the ECGs (13 in the patients with LMNA variants and 10 in the non-LMNA group). The likelihood of having an arrhythmia was significantly higher in the patients with LMNA variants versus those without (odds ratio of 3.4, CI: 1.1–10.6). DISCUSSION/SIGNIFICANCE OF IMPACT: The overall prevalence of abnormal ECHO and/or ECG is high at 45/58 (78 %) in FPLD. Patients with LMNA variants have a 3.4 times increased risk of developing cardiac arrhythmias compared to those without. We recommend vigilant, monitoring for cardiac disease in FPLD and for arrhythmias in patients with FPLD and LMNA variants.

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Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene

Journal of Clinical Medicine ◽

10.3390/jcm10061259 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1259

Author(s):

David Araújo-Vilar ◽

Sofía Sánchez-Iglesias ◽

Ana I. Castro ◽

Silvia Cobelo-Gómez ◽

Álvaro Hermida-Ameijeiras ◽

...

Keyword(s):

Body Composition ◽

Skinfold Thickness ◽

Pathogenic Variant ◽

The Other ◽

Metabolic Abnormalities ◽

Lmna Gene ◽

Partial Lipodystrophy ◽

Variable Expressivity ◽

Familial Partial Lipodystrophy

Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.

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