SUN-593 Variants in Known Monogenic Causal Genes of Hypertriglyceridemia Are Not Major Contributors for Hypertriglyceridemia in Lipodystrophy Due to a LMNA Mutation
Notice bibliographique
Résumé
Abstract Background: Lipodystrophy is a heterogeneous disorder of adiposity, and one common lipid manifestation is hypertriglyceridemia (HTG). The LMNA gene, which encodes for nuclear envelope proteins, is a known causal gene for heritable lipodystrophy. At present, underlying mechanisms for each clinical manifestation of lipodystrophy due to a LMNA mutation are unknown. Hypothesis: A likely explanation for HTG in lipodystrophy is the paucity of adipose tissue where excess triglycerides (TGs) are normally stored, thus it may not be due to a specific defect in lipoprotein metabolism. Consequently, rare variants in HTG-associated genes would not be expected to be major contributors for HTG in lipodystrophy with LMNA mutations. Method: A proband and her father with a clinical diagnosis of lipodystrophy were recruited into an IRB-approved study investigating molecular etiologies of dyslipidemia at the University of Pennsylvania. Next-generation sequencing (NGS) with the LipidSeq panel, targeting causal genes for lipodystrophy, and monogenic HTG was performed, and confirmed by Sanger sequencing. Also, unweighted TG-polygenic scores by summing the number of TG-raising alleles from 14 single nucleotide polymorphisms (SNPs) associated with TG levels were assessed. Results: The proband and her father were diagnosed with lipodystrophy of two different subtypes, generalized in the daughter and partial in the father. The proband reported a gradual loss of subcutaneous fat starting around age 10. A highest reported TG in the proband was19,000 mg/dL with eruptive xanthomas, whereas TG in the father was never >500 mg/dL. Their BMI’s and DEXA body fat% were 12.9 kg/m2 and 7% in the proband, and 25.7 kg/m2 and 25% in the father, corresponding to their fat storage capacities. The molecular analyses revealed only a lipodystrophy causal mutation in LMNA, c.29C>T, T10I with no other significant findings in18 other lipodystrophy-related genes. No deletion or duplication was identified by a targeted array CGH of LMNA. As predicted, no rare monogenic variants in HTG-causal genes (LPL, GPIHBP1, APOA5, APOC2, LMF1, GPD1) were identified in either subject. However, TG-polygenic scores were 17/28 (95th %ile) in the proband, and 13/28 (50th %ile) in the father, the same trend as the level of HTG levels seen in them. Apolipoprotein E genotypes were non-contributory, (3/3) in the proband, and (3/4) in the father. Conclusion: Our findings support that the pathophysiology of HTG in lipodystrophy is likely to be due to lack of TG-storage space (adipose tissues), and is unlikely due to a defect in lipoprotein metabolism seen in patients with rare monogenic HTG-variants. Although the HTG-polygenic score was higher in the proband, and the accumulative effects of the at-risk alleles may be contributor to the HTG phenotype, it is unlikely to be the leading cause of severe HTG seen in the proband.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».