Background

DGAT1, a gene encoding a protein involved in lipid metabolism, has been recently implicated in causing a rare nutritional and digestive disease presenting as Congenital Diarrheal Disorder (CDD). Genetic causes of malnutrition can be classified as metabolic disorders, caused by loss of a specific enzyme's function. However, disease driven by genetic variants in lipid metabolism genes is not well understood, and additional information is needed to better understand these effects.

Methods

We gathered a multi-institutional cohort of undiagnosed patients with a constellation of phenotypes presenting as malnutrition and metal ion dysregulation. Clinical Whole Exome Sequencing (WES) was performed on four patients and their unaffected parents. We prioritized genetic variants based on multiple criteria including population allele frequency and presumed inheritance pattern, and identified a candidate gene. Computational modeling was used to investigate if the altered amino acids are likely to result in a dysfunctional enzyme.

Results

We identified a multi-institutional cohort of patients presenting with malnutrition-like symptoms and likely pathogenic genomic variants within DGAT1. Multiple approaches were used to profile the effect these variants have on protein structure and function. Laboratory and nutritional intervention studies showed rapid and robust patient responses.

Conclusions

This report adds on to the database for existing mutations known within DGAT1, a gene recently implicated with CDD, and also expands its clinical spectrum. Identification of these DGAT1 mutations by WES has allowed for changes in the patients’ nutritional rehabilitation, reversed growth failure and enabled them to be weaned off of total parenteral nutrition (TPN).

中文翻译：

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DGAT1中的遗传变异通过特定的分子机制引起营养不良的多种临床表现。

背景

DGAT1是一种编码参与脂质代谢的蛋白质的基因，最近与导致一种罕见的营养和消化系统疾病有关，该疾病表现为先天性腹泻病（CDD）。营养不良的遗传原因可以归为代谢性疾病，是由特定酶功能的丧失引起的。但是，由脂质代谢基因的遗传变异驱动的疾病尚不十分清楚，因此需要更多信息以更好地理解这些作用。

方法

我们收集了多个机构的未诊断患者队列，这些患者的表型呈营养不良和金属离子失调。对四名患者及其未受影响的父母进行了临床全基因组测序（WES）。我们基于包括人口等位基因频率和假定的遗传模式在内的多个标准对遗传变异进行了优先排序，并确定了候选基因。计算模型用于研究氨基酸的改变是否可能导致酶功能异常。

结果

我们确定了多机构队列的患者，这些患者在DGAT1中出现营养不良样症状和可能的致病基因组变异。使用多种方法来分析这些变体对蛋白质结构和功能的影响。实验室和营养干预研究显示出快速而有力的患者反应。

结论

该报告将数据库DGAT1中已知的现有突变添加到数据库中，DGAT1是最近与CDD相关的基因，并且还扩大了其临床范围。通过WES鉴定这些DGAT1突变，可以改变患者的营养状况，逆转生长衰竭，使他们可以摆脱总肠胃外营养（TPN）。