未经证实:Alport综合征是一种以血尿为特征的遗传性肾小球病,蛋白尿,和进行性肾衰竭.由COL4A5引起的X连锁Alport综合征(XLAS)是最常见的形式。在由10-18%假定的从头COL4A5致病变异产生的XLAS的情况下,只有少数关于先证者或父母镶嵌的研究。COL4A5致病变异的极低水平(<1.0%)的体细胞镶嵌尚未发表。
未经授权:本研究纳入了怀疑父母镶嵌的中国XLAS家庭,以评估镶嵌的形式,提供更合适的遗传咨询。PCR和直接测序用于检测亲本多组织DNA中受影响的先证者所携带的COL4A5致病变异(外周血,尿液沉积物,唾液,头发),和液滴数字PCR(ddPCR)用于定量突变COL4A5等位基因部分在亲本不同的样品,如外周血,唾液,还有尿液沉淀物.
UNASSIGNED:一名疑似体细胞和种系镶嵌的中国无症状女性被纳入本研究。她生下了两个由半合子致病变异c引起的XLAS男孩。COL4A5(NM_033380)内含子28中的2245-1G>A,而使用Sanger测序从女性外周血白细胞中提取的基因组DNA中未检测到这种致病变异。她有多项正常的尿检结果,和皮肤组织的α2(IV)和α5(IV)链的连续线性免疫荧光染色。Sanger测序表明,在从尿液沉积物中分离出的基因组DNA中未检测到COL4A5致病变异c。2245-1G>A,唾液,和发根。使用ddPCR,在从外周血中分离的女性基因组DNA中鉴定出野生型和突变型(c.2245-1G>A)COL4A5,唾液,还有尿液沉淀物.这些组织中的突变等位基因分数为0.26%(外周血),0.73%(唾液),和1.39%(尿液),分别。
UNASSIGNED:在无症状女性中检测到COL4A5剪接变体的种系和极低水平的体细胞镶嵌,这突出表明,当检测到COL4A5推测的从头致病变异体时,应排除亲本镶嵌性。
UNASSIGNED: Alport syndrome is a hereditary glomerulopathy featured by haematuria, proteinuria, and progressive renal failure. X-linked Alport syndrome (XLAS) due to COL4A5 disease-causing variants is the most common form. In the case of XLAS resulting from 10-18% presumed de novo COL4A5 disease-causing variants, there are only a few studies for mosaicism in the probands or parents. Very low-level (<1.0%) somatic mosaicism for COL4A5 disease-causing variants has not been published.
UNASSIGNED: Chinese XLAS families with suspected parental mosaicism were enrolled in the present study to evaluate the forms of mosaicism, to offer more appropriate genetic counseling. PCR and direct sequencing were used to detect COL4A5 disease-causing variants harbored by the affected probands in parental multi-tissue DNAs (peripheral blood, urine sediments, saliva, hair), and droplet digital PCR (ddPCR) was used to quantify the mutant COL4A5 allelic fractions in parental different samples such as peripheral blood, saliva, and urine sediments.
UNASSIGNED: A Chinese asymptomatic female with suspected somatic and germline mosaicism was enrolled in the present study. She gave birth to two boys with XLAS caused by a hemizygous disease-causing variant c. 2245-1G>A in COL4A5 (NM_033380) intron 28, whereas this disease-causing variant was not detected in genomic DNA extracted from peripheral blood leukocytes in the woman using Sanger sequencing. She had multiple normal urine test results, and continuous linear immunofluorescence staining of α2 (IV) and α5 (IV) chains of skin tissue. Sanger sequencing demonstrated that COL4A5 disease-causing variant c. 2245-1G>A was not detected in her genomic DNAs isolated from urine sediments, saliva, and hair roots. Using ddPCR, the wild-type and mutant-type (c.2245-1G>A) COL4A5 was identified in the female\'s genomic DNAs isolated from peripheral blood, saliva, and urine sediments. The mutant allelic fractions in these tissues were 0.26% (peripheral blood), 0.73% (saliva), and 1.39% (urine), respectively.
UNASSIGNED: Germline and very low-level somatic mosaicism for a COL4A5 splicing variant was detected in an asymptomatic female, which highlights that parental mosaicism should be excluded when a COL4A5 presumed de novo disease-causing variant is detected.