背景:发作性睡病1型(NT1)是一种罕见的慢性神经系统疾病,其特征是突然的睡眠发作,压倒性的白天嗜睡,还有猝倒.当与突然的肌张力丧失(猝倒)相关时,发作性睡病被归类为1型,而没有猝倒则表示2型。遗传,退化,和解释NT1病理生理学的免疫学假设仍然存在争议。为了有助于理解NT1的遗传基础,在这里我们描述,第一次,对NT1不一致的单卵双胞胎对的全基因组分析。
方法:我们介绍了一对17岁的男性,同卵双生子与NT1不一致。受影响的双胞胎的Epworth嗜睡量表(ESS)为20(范围从0到24),猝倒,催眠幻觉,多导睡眠图没有异常,发作性睡病的多次睡眠潜伏期测试(MSLT)呈阳性,平均睡眠潜伏期为3分钟,睡眠开始的REM期SOREMPs为5,等位基因HLA-DQB1*06:02的存在,以及hypocretin-1水平为0pg/mL(正常值>200pg/mL)。另一个双胞胎没有发作性睡病症状(ESS为4),正常多导睡眠图,MSLT无异常,等位基因HLA-DQB1*06:02的存在,以及396,74pg/mL的Hypocretin-1水平。为了描述这种情况下NT1不一致表现的遗传背景,我们介绍了这对单卵双胞胎的全基因组分析.全基因组比较显示,两个双胞胎在已知基因中都有相同的NT1致病突变,例如HLA-DQB1*06:02:01、HLA-DRB1*11:01:02/*15:03:01。受影响的双胞胎具有预期的临床表现,而未受影响的双胞胎具有意外的表型。与受影响的双胞胎相比,未受影响的双胞胎具有明显更多的移码突变(108对75)和影响终止密码子的突变(停止增益为61对5,26对2开始输了)。
结论:在未受影响的双胞胎中观察到的移码和终止密码子突变的差异与功能丧失效应和保护性等位基因一致,几乎总是与功能丧失的罕见等位基因有关。此外,在未受影响的双胞胎中,对含有具有潜在临床相关性的变异的基因的过度表达分析表明,大多数突变是在与免疫调节功能相关的基因中,高尔基体,MHC,和嗅觉受体。这些观察结果支持NT1具有免疫学基础的假设,尽管非HLA等位基因中的保护性突变可能会干扰NT1表型的表达,因此,与该病的临床表现有关。
BACKGROUND: Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. When associated with a sudden loss of muscle tone (cataplexy) narcolepsy is classified as type 1, while the absence of cataplexy indicates type 2. Genetic, degenerative, and immunological hypotheses to explain the pathophysiology of NT1 are still a matter of debate. To contribute to the understanding of NT1 genetic basis, here we describe, for the first time, a whole genome analysis of a monozygotic twin pair discordant for NT1.
METHODS: We present the
case of a pair of 17-year-old male, monozygotic twins discordant for NT1. The affected twin had Epworth Sleepiness Scale (ESS) of 20 (can range from 0 to 24), cataplexy, hypnagogic hallucinations, polysomnography without abnormalities, multiple sleep latency tests (MSLT) positive for narcolepsy, a mean sleep latency of 3 min, sleep-onset REM periods SOREMPs of 5, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of zero pg/mL (normal values are > 200 pg/mL). The other twin had no narcolepsy symptoms (ESS of 4), normal polysomnography, MSLT without abnormalities, presence of allele HLA-DQB1*06:02, and Hypocretin-1 level of 396,74 pg/mL. To describe the genetic background for the NT1 discordant manifestations in this
case, we present the whole-genome analysis of this monozygotic twin pair. The whole-genome comparison revealed that both twins have identical NT1 pathogenic mutations in known genes, such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01. The affected twin has the expected clinical manifestation while the unaffected twin has an unexpected phenotype. The unaffected twin has significantly more frameshift mutations as compared to the affected twin (108 versus 75) and mutations that affect stop codons (61 versus 5 in stop gain, 26 versus 2 in start lost).
CONCLUSIONS: The differences observed in frameshift and stop codon mutations in the unaffected twin are consistent with loss-of-function effects and protective alleles, that are almost always associated with loss-of-function rare alleles. Also, overrepresentation analysis of genes containing variants with potential clinical relevance in the unaffected twin shows that most mutations are in genes related to immune regulation function, Golgi apparatus, MHC, and olfactory receptor. These observations support the hypothesis that NT1 has an immunological basis although protective mutations in non-HLA alleles might interfere with the expression of the NT1 phenotype and consequently, with the clinical manifestation of the disease.