METHODS: Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations.
RESULTS: Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%.
CONCLUSIONS: This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.
方法:对每位患者进行临床评估和全外显子组测序。在治疗前后进行代谢谱分析,在可能的地方。通过使用Sanger测序的分离分析来建立变体的隐性遗传和阶段。最后,在4个最大的SA群体中确定了2个主要变异体的单倍型和等位基因频率.
结果:在14名受影响的个体中观察到12个不相关的家庭(10个白人SA和2个混合种族)的临床异质性表现,并鉴定出5种致病性ETFDH变异体。根据疾病的严重程度和治疗反应,出现了三个不同的群体。最严重和致命的表现与纯合c有关。[1067G>A];c。[1067G>A]和复合杂合c.[976G>C];c.[1067G>A]基因型,导致MADDI型和I/II型,分别。这些,以及三种不太严重的复合杂合基因型(c。[1067G>A];c。[1448C>T],c.[740G>T];c.[1448C>T],和c。[287dupA*];c。[1448C>T]),导致MADDII/III型,在五岁之前提出的,取决于干预的时间和维护。相比之下,纯合c.[1448C>T];c.[1448C>T]基因型,导致MADDIII型,在以后的生活中。除了I型,I/II和II案例,使用核黄素和L-肉碱治疗后,MADD的尿代谢标志物得到改善/正常化。此外,最常见变异的遗传分析(c.[1067G>A]和c。[1448C>T])揭示了ETFDH区域中的共享单倍型,SA群体特异性等位基因频率<0.00067-0.00084%。
结论:这项研究揭示了来自不同和未被研究的SA人群的MADD患者队列的第一个广泛的基因型-表型特征。致病性变异和相关的可变表型进行了表征,这将使早期筛查,遗传咨询,以及该人群中MADD的患者特异性治疗。