New upgrade! CNV-seq can detect triploid and fragment level UPD
Chromosome abnormality is a major factor leading to birth defects. There are many technologies to detect chromosomal abnormalities. In recent years, genome copy number variation technology based on high throughput sequencing is widely used in clinical applications, such as abortion cause investigation, prenatal diagnosis and genetic etiology detection. However, CNV-seq has it’s limitation in prenatal diagnosis and genetic etiology detection. The mainly reason is that CNV-seq cannot detect triploid and Uniparental Disomy(UPD). Therefore, it is advised by the consensus guideline that CNV-seq should be combined with other technology to detect triploid and UPD to prevent misdiagnose.
Based on the consideration of clinical requirement, Basecare upgraded CNV-seq product and adopted special library construction method to realize the detection of triploid and more than 5MB heterozygosity in combination with SNP information, provide more cost-effective testing products with the same detection content as common chips.
New launch of upgraded CNV-seq
●23 pairs of chromosome aneuploidy
●Deletion / duplication of chromosome fragments above 100kb
●Newly added triploid detection
●Newly added detection for AOH or UPD above 5MB
●Upgrade≥10% Detection of chromosome aneuploidy chimerism
●Upgrade≥20% Detection of chromosome segments chimerism of more than 10MB
Introduction of CNV-seq
The detection of Triploid and UPD chromosome abnormalities are with same importance
Triploidy has a certain proportion in the chromosomal etiology of miscarriage. The study revealed that about 0.5% abortion is caused by chromosomal triploid abnormalities. Meanwhile, detection of triploid is of great guiding meaning to the following child bearing and can affect the design of future assisted reproduction scheme and the selection of prenatal diagnosis technology.
In the detection of chromosome abnormalities, chromosomal number abnormalities and fragment deletion and duplication are the main focus of clinics while AOH or UPD are ignored or even forgotten. The reason is as follows, first, lack of related knowledge, even cannot say its Chinese name in a correct way or tell the difference between AOH and UPD, Second, The late startup of AOH and UPD detection technology in clinical. AOH refers to the loss of heterozygosity in the genomic regions. UPD ours when a chromosome segment from one parent is replaced by a homologous part from the other, or when both homologous chromosomes of one individual come from the same parent. There are imprinted genes on these chromosomes when UPD occurs on chromosome 6,7,11,14,15 and 20, which may result in the occurrence of UPD disease. UPD disease is very important in many disease such as abnormal prenatal fetal development, child mental retardation and growth retardation. The incidence of UPD is not low, about 1/4000, lower than trisomy 21 syndrome, but higher than Trisomy 18 and Trisomy 13
CNV-seq consensus suggests combing other technologies to assist in the diagnosis of UPD
In April 2019, the clinical genetics group of the medical genetics branch of the Chinese Medical Association, the genetic disease prenatal diagnosis Professional Committee of the medical genetics branch of the Chinese Medical Association, and the genetic disease prevention and control group of the birth defect prevention and Control Professional Committee of the Chinese Preventive Medicine Association jointly issued the expert consensus on the application of low depth whole genome sequencing technology in the prenatal diagnosis. It recommended that STR or SNP array technology should be combined for the testing when there is a high degree of clinical suspicion of uniparental disomy.
2020 ACMG statements on the consideration of prenatal diagnosis of UPD
ACMG guideline issued statement of UPD prenatal diagnosis under the general situation that SNP chips are gradually replaced by CNV-seq, suggesting that UPD should be detected in prenatal diagnosis for the following groups: pregnant women with advanced maternal age; PGT assisted pregnancy with the intention to implant imprinted chromosomal chimeric embryos; Villus or amniocentesis suggested imprinted chromosome trisomy or monomer chimerism; Prenatal ultrasound abnormalities are consistent with a phenotype of UPD disease; Villus or amniocentesis indicates the presence of inherited or new Roche translocation or isochromosome involving chromosome 14 or 15; New mall marker chromosome without euchromation; The 3:1 segregation of imprinted chromosomes occurring in non-Roche translocations may lead to trisomy or monosomy rescue or gamete rescue.
The Expert Consensus on data interpretation and report standardization of CNV and AOH in prenatal genetic diagnosis recommended the detection of AOH above 5Mb
The group standard suggests that the detection threshold of AOH is AOH above 5Mb, which not only describes the situation of reporting UPD, also suggests that for non-imprinted chromosomes, it’s necessary to report AOH and accept extra testing if the AOH region contains genes related to Mendelian recessive genetic disease with severe consequences and the phenotype indicated by ultrasound is consistent with the disease or there is a family history of related diseases.
Our upgraded CNV-seq can achieve the detection efficiency of gene chips for pediatric genetic diseases.
In June 2016, The expert consensus on the clinical application of chromosome genomic chip in pediatric genetic diseases jointly issued by the Medical Genetics Branch of the Chinese Medical Association, the Clinical Genetic Group of the Adolescent Medical Professional Committee of the Chinese Medical Association and the Metabolism Group of the Pediatrics Branch of the Chinese Medical Association suggested CMA testing for unexplained mental retardation, growth retardation, multiple malformations of unknown syndromes and Autism spectrum disorder. The basic parameter of the CMA should meet the following requirements: the probe covers the region of recurrent genomic diseases and common microdeletion and microduplication syndrome; can detect more than 400Kb CNV; can detect the homozygous regions of known imprinted area (AOH). The upgraded CNV-seq product can meet the requirements of consensus on chromosome abnormality detection.
 The Clinical Genetic Group of Medical genetics branch of Chinese Medical Association. Professional Committee for prenatal Diagnosis of Genetic Diseases of Medical genetics branch of Chinese Medical Association, Genetic Disease Prevention and Control Group of Birth Defect Prevention and Control Professional Committee of Chinese Preventive Medicine Association. Expert Consensus on the application of low depth whole genome sequencing in prenatal diagnosis[J]. Chinese Journal of Medical Genetics,2019; 36(4): 293-296.
 Wang Y, Li Y, Chen Y, Zhou R, Sang Z, Meng L, Tan J, Qiao F, Bao Q, Luo D, Peng C, Wang YS, Luo C, Hu P, Xu Z. Systematic analysis of copy-number variations associated with early pregnancy loss. Ultrasound Obstet Gynecol. 2020 Jan;55(1):96-104.
 Benn P. Uniparental disomy: Origin, frequency, and clinical significance. Prenat Diagn. 2021 Apr;41(5):564-572.
 Daniela Del Gaudio, et al. Diagnostic Testing for Uniparental Disomy: A Points to Consider Statement From the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020; 22(7): 1133-1141.
Medical genetics branch of Chinese Medical Association. The Clinical Genetic Group of the Adolescent Medical Professional Committee of the Chinese Medical Association. The Metabolism Group of the Pediatrics Branch of the Chinese Medical Association. Expert Consensus on the Application of Chromosome Chips in Pediatric Genetic Diseases[J]. Chinese Journal of Pediatrics 54(6)June 2016.