Laboratory Medicine

Application prospects and challenges of genetic testing in the diagnosis of rare disorders

GUO Wei

2025, 40(2): 105-108. DOI: 10.3969/j.issn.1673-8640.2025.02.001

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The advent of the era of precision medicine has opened up a new diagnosis and treatment model for rare disorders，and the development of multi-omics technology has also promoted the research and clinical application of precise phenotypes of rare disorders. The rapid development of genetic testing technology has improved the diagnostic efficiency of rare disorders and provides a molecular biological basis for their subsequent precision treatment. How to seize this opportunity to promote the development of rare disorder diagnosis and treatment，how to make genetic testing technology more efficiently in the clinic，benefit rare disorder patients and families，and achieve early diagnosis and treatment of rare disorders，deserve attention. Starting with the difficulties in the diagnosis and treatment of rare disorders and the application prospects of genetic testing technology in the diagnosis and treatment of rare disorders，this paper focuses on the challenges in the application process and proposes a popular application model.

Consideration and application of improving the positive detection rate of rare genetic disorders

MA Duan

2025, 40(2): 109-113. DOI: 10.3969/j.issn.1673-8640.2025.02.002

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Approximately 80% of rare disorders are associated with genetic variations. Although gene sequencing has emerged as the primary approach for identifying genetic variations，the current average positive detection rate remains below 40%，falling short of clinical requirements. This review aims to improve the detection rate of mutant genes by integrating fundamental concepts and recent advancements in several key areas，such as gene coding regions，non-coding regions，DNA methylation，post-detection analysis and gene reanalysis. It aims to propose strategies and methodologies that may contribute to more effective clinical gene detection.

Quality control and proficiency testing in next-generation sequencing of inherited genetic mutations

WANG Yange, YANG Jiyun, ZHOU Yu, JIANG Li

2025, 40(2): 114-120. DOI: 10.3969/j.issn.1673-8640.2025.02.003

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Next-generation sequencing（NGS） provides technical support for the precise detection of genetic mutations associated with hereditary diseases and their diagnosis. However，the accuracy and validity of NGS are susceptible to various factors，including sample quality，experimental procedures，instrument performance and datum analysis processes. Therefore，clinical laboratories must implement comprehensive quality control measures to guarantee the validity of the detection results. This review focuses on the quality control strategies and proficiency testing（PT） methods in the NGS workflow，providing a reference for standardized laboratory management of NGS.

Clinical phenotype and molecular genetic characteristics of adult Krabbe disease in China

WANG Guoyu, ZHAI Jianzhao, ZHONG Huiyu, LIU Tangyuheng, JIAO Lin, HE Yong, YING Binwu, WANG Minjin

2025, 40(2): 121-130. DOI: 10.3969/j.issn.1673-8640.2025.02.004

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Objective To review the literatures on the clinical phenotype and molecular genetic characteristics of adult Krabbe disease（KD） in China，so as to improve the ability of clinical diagnosis. Methods From January 2020 to November 2024，89 patients with suspected genetic leukoencephalopathy（GLES） in West China Hospital of Sichuan University were screened for whole-exome sequencing，5 patients with adult KD were enrolled，and their clinical data were analyzed retrospectively. By retrieving literatures，the clinical phenotype and molecular genetic characteristics of adult KD in China were summarized and analyzed. Results One of the 5 cases presented with mental disorder and mental decline. Mental disorder was the first clinical symptom. Two unreported mutations，c.1164_1165del and c.581G>T，were identified in the 5 cases，and c.1164_1165del may be likely pathogenic，while mental disorder was the first clinical symptom in patients with c.581G>T. A total of 15 literatures were searched for 27 adult KD patients. A total of 32 Chinese patients with adult KD were reviewed. The main clinical symptoms were walking difficulty and gait disturbance（80.0%），peripheral nerve damage（60.0%） and spastic paralysis（40.0%）. The common findings of nervous system examination were decreased muscle strength，hypertonia，hyperreflexia and positive pathological signs of lower limbs. Electromyography showed abnormal conduction of motor and sensory nerves. Most of the imaging examinations showed T2 hyperintensity，which was common in the white matter and corticospinal tract area. Genetic analysis revealed 29 GALC mutations，the most common one was c.1901T>C，the second one was c.136G>T. Conclusions The c.1901T>C is the most common mutation of adult KD in Chinese. The clinical symptoms are often characterized by walking difficulty and gait disturbance and peripheral nerve damage. The clinical symptoms of KD patients with different mutation sites and genotypes are diverse. KD should be considered in patients with seizure，mental disorder，mental decline and unknown etiology who have neuroimaging changes of white matter lesions. Genetic testing can confirm the diagnosis.

Genetic analysis of a child with small supernumerary marker chromosomes by chromosomal microarray analysis

ZHANG Xia, YIN Yanjun, FU Zhixuan, KE Jiangwei

2025, 40(2): 131-134. DOI: 10.3969/j.issn.1673-8640.2025.02.005

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Objective To analyze the origin of small supernumerary marker chromosomes（sSMC） of a mental decline and developmental delay child，and to investigate its mechanism and provide a reference for clinical genetic counseling. Methods Peripheral blood of the child and her parents was analyzed with conventional G-banding. Chromosomal microarray analysis（CMA） was performed to analyze the whole-genome copy number variations（CNV） in order to identify the origin，region and size of sSMC. Results The karyotype of the parents was normal，and the karyotype was 47，XX，+mar. CMA showed that the child had a duplication of 9.7 Mb in chr15q11.2q13.3（copy number was 4），which was clinical pathogenic CNV correlating with dup（15） syndrome. Conclusions Because of the diversity of the origin of sSMC，it is necessary to combine CMA with traditional chromosome karyotype analysis to identify the origin，region and size of sSMC，so as to provide a reference for the diagnosis，treatment and clinical genetic counseling for children.

Genetic analysis of a case of ring chromosome 18 child and literature review

HUANG Bingyi, ZHAO Qin, YU Donglan, WANG Manyi, ZHU Chunjiang

2025, 40(2): 135-141. DOI: 10.3969/j.issn.1673-8640.2025.02.006

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Objective To conduct a genetic analysis on a child with mental decline and delayed growth and development，and to analyze the relationship between clinical phenotype and genetic characteristics. Methods The clinical data from the patient with mental decline and delayed growth and development were collected. G-banding karyotype analysis and copy number variation sequencing（CNV-seq） were performed. Using "ring chromosome 18" as the keyword，the papers included in China National Knowledge Infrastructure，Wanfang Data Knowledge Service Platform and PubMed were searched from January 1998 to October 2024. The clinical manifestations and chromosomal karyotype analysis results of patients with ring chromosome 18 were summarized. Results The child had a distinctive facial appearance，and the chromosomal karyotype analysis result was 46，XY，r（18）（p11.21q23）. The CNV-seq result was seq[hg19]del（18）（p11.32p11.21）chr18：g.120000_14980000del，indicating a 14.86 Mb copy number deletion in the 18p11.32p11.21 region，diagnosed with ring chromosome 18. The chromosomal karyotypes of the child's parents were both normal. A total of 16 papers on ring chromosome 18 were searched（16 cases）. Among the 17 patients，distinctive facial appearance accounted for 100.00%（17/17），mental decline accounted for 93.75%（15/16，excluding one prenatally diagnosed fetus），language and behavioral delays accounted for 64.71%（11/17），short stature accounted for 52.94%（9/17），neurodevelopmental abnormalities accounted for 41.18%（7/17），microcephaly accounted for 17.65%（3/17），cardiac anomalies accounted for 23.53%（4/17），endocrine and immune system abnormalities accounted for 17.65%（3/17），hypotonia accounted for 17.65%（3/17），ocular abnormalities accounted for 17.65%（3/17），epilepsy accounted for 11.76%（2/17），gonadal dysgenesis accounted for 11.76%（2/17），and skin lesions accounted for 5.88%（1/17）. Conclusions Children with ring chromosome 18 may present with manifestations such as delayed growth and development，mental decline，distinctive facial appearance，neurodevelopmental abnormalities and cardiac anomalies. Their clinical phenotypes are related to the location of the chromosome deletion and the size of the deleted segment.

Clinical characteristic and genetic analysis of a new mutation of SF3B4 gene causing neonatal acrofacial dysostosis 1，Nager type

WANG Binbin, LI Fengqi, GUO Fenglian, ZHANG Rui, KANG Huihui, WANG Yuetong

2025, 40(2): 142-147. DOI: 10.3969/j.issn.1673-8640.2025.02.007

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Objective To investigate the clinical characteristics and genetic etiology of a neonatal acrofacial dysostosis 1，Nager type. Methods Trio-whole-exome sequencing was performed on the patient and her parents，and Sanger sequencing was used for verification. Bioinformatics was used to analyze the pathogenicity of variation. Mutant plasmids were constructed in vitro to observe protein overexpression levels. Results The neonate exhibited distinctive facial appearance at birth，which included downslanting eyelids，ptosis，low-set ears and mandibular hypoplasia，accompanied by neonatal respiratory failure and acidosis. Genetic testing results revealed a frameshift variation in SF3B4 gene，c.980dup（p.G328Rfs*158），which was not present in the parents. The variation was not found in public variation database（dbSNP，1000 Genomes and ExAC）. A search of PubMed and HGMD databases revealed no previous reports of the variation，indicating it is a new variation in SF3B4. The mutated protein was almost not expressed compared to wild-type，indicating that the mutated protein may be degraded caused by SF3B4 c.980dup（p.G328Rfs*158）. Conclusions The clinical characteristics of the patient may be caused by SF3B4 c.980dup（p.G328Rfs*158）. Early molecular diagnosis should be made for children with distinctive facial appearance such as mandibular hypoplasia.

Whole-genome sequencing in health management of physical examination population

GAO Yaoyi, ZHANG Li, WEI Zhiying, SHEN Minna, ZHANG Huayang, ZHANG Chunyan, PAN Baishen, WANG Beili, GUO Wei

2025, 40(2): 148-153. DOI: 10.3969/j.issn.1673-8640.2025.02.008

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Objective To investigate the benefits of whole-genome sequencing（WGS） in physical examination population. Methods A total of 70 subjects who underwent WGS at Zhongshan Hospital of Fudan University from March 2023 to July 2024 for physical examination were enrolled. The general data were collected，and bioinformatics analysis was performed on the sequencing data. The pathogenicity of the detected mutations was analyzed using the sequence variation interpretation guidelines developed by American College of Medical Genetics and Genomics（ACMG）. Results A total of 390 genetic variations were detected in 70 subjects undergoing physical examination，which included 69 pathogenic variations（17.7%） and 76 suspected pathogenic variations（19.5%）. In 16 cases（22.9%），19 variations that can cause monogenic genetic diseases were detected. Totally，60 cases（85.7%） were detected with at least one pathogenic or suspected pathogenic variation associated with recessive genetic diseases or X-linked genetic diseases. The top 5 genes with high detection rates were GJB2（6.67%），HFE（4.17%），DUOX2（3.33%），SLC26A4（3.33%） and SERPINB7（2.50%）. Among the 70 subjects who underwent physical examination，5（7.14%），2（2.86%），1（1.43%），1（1.43%），1（1.43%） and 1（1.43%） of them were found to be at high genetic risk for Alzheimer's disease，ankylosing spondylitis，Sjogren's syndrome，gallstones，prostate cancer and multiple myeloma，respectively. Another 2 subjects（2.86%） and 1 subject（1.43%） were found to have low genetic risk for psoriasis and cataracts，respectively. The 100% subjects will not respond or experience adverse reactions to at least one medication. Conclusions The physical examination subjects in this study can benefit to various degrees from WGS. The further promotion of WGS in physical examination population may help with disease prevention and health management throughout their entire life cycle.

Neurofibromatosis type 1 with CDK13-related disorder：a case report and literature

LU Yaya, WANG Yaqiong, PENG Huifang, LOU Dan

2025, 40(2): 154-159. DOI: 10.3969/j.issn.1673-8640.2025.02.009

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Objective To investigate the clinical phenotypes and genetic characteristics of neurofibromatosis type 1（NF1） gene and cell cycle-dependent protein kinase 13（CDK13） gene. Methods The clinical data of a patient who was diagnosed with NF1 combined with CDK13-related disorder were collected retrospectively. Whole-exome sequencing was performed for the child and parents. The suspected variation was verified by Sanger sequencing and analyzed by connoisseur. Using "CDK13 gene and NF1 gene" as the keywords，relevant literatures were searched at CNKI，Wanfang Data and PubMed from the establishment of databases to February 2024. The clinical and genetic characteristics of this case of NF1 combined with CDK13-related disorder were summarized. Results The main clinical manifestations included café-au-lait macules，short stature，distinctive facial appearance（upslanting palpebral fissures，ocular hypertelorism，epicanthus and broad nasal bridge） and mental retardation. Whole-exome sequencing showed a heterogeneous variation CDK13 c.484dupG，p.Ala162Glyfs*108，NF1 c.3610C>G，p.Arg1204Gly. Sanger sequencing showed that the mother of the child carried a heterozygous mutation of NF1 gene，but did not carry a frameshit mutation of CDK13 gene. No literature with NF1 and CDK13-related disorder were found. A total of 11 papers were collected. The clinical manifestations of 97 patients were mental retardation or developmental delay，distinctive facial appearance and congenital heart defect. The main pathogenic variations were missense mutations. Conclusions NF1 gene mutation is the cause of NF1. Coexistence of double genetic diseases should be considered when NF1 patients with distinctive facial appearance and the existing phenotype or symptoms cannot be explained.

Result analysis of external quality assessment of next-generation sequencing for genetic testing of inherited diseases in Shanghai

BAO Yun, YU Tingting, QUAN Jing, YIN Liufan, ZHANG Pengyin, XIAO Yanqun

2025, 40(2): 160-164. DOI: 10.3969/j.issn.1673-8640.2025.02.010

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Objective To evaluate the performance of next-generation sequencing for genetic testing of inherited diseases in external quality assessment（EQA） program and improve the quality of detection results. Methods In 2024 EQA program，3 different neurogenetic disorders including Prader-Willi syndrome（PWS），Duchenne muscular dystrophy（DMD） and Huntington's disease（HD） were investigated. Totally，2 types of genetic variations of copy number variations（CNV） and dynamic mutations were involved. The sample panel consisted of 3 different cell cultures. Participating laboratories were asked to report the results before deadlines. The overall coincidence of detection and report of the pathogenic variations were calculated，and the basic next-generation sequencing conditions，wet-lab procedure，bioinformatics analysis workflow，quality control measures were also analyzed. Results A total of 16 laboratories enrolled in the EQA program and 11 valid laboratory results were received in the EQA program. The coincidence rate of CNV and dynamic mutations were 100.0%（22/22） and 81.8%（9/11），respectively. The overall coincidence rates were 93.9%（31/33）. Among the 11 laboratories that returned valid results，8（72.7%） completed both "wet lab" and "dry lab" procedure independently，while the other 3 laboratories had different levels of testing outsourcing. The 9（81.8%） employed whole-exome sequencing（WES），and 2（19.2%） used whole-genome sequencing（WGS）. The detection scope of all 11 laboratories covered single nucleotide variations（SNV），small insertions-deletion（InDel），as well as CNV，but varied in CNV detection range. The overall quality of sequencing data for all the 33 samples was high，with the proportion of sequencing data meeting the Q30 standard ranging from 91.60% to 96.91%. The probe capture efficiency of the 27 samples for WES varied（49.20%-87.91%）. All the 11 laboratories specified the minimum concentration of sequencing libraries，but the quality control requirements for other steps varied. Conclusions Some laboratories in Shanghai need to enhance their detection capabilities for specific mutation types. There is a need for additional improvements in the experimental procedure as well as quality control of NGS applications for detecting genetic variations.

Molecular epidemiological analysis of patients with increased stomatocytes and giant platelets in peripheral blood

ZHOU Jiakuan, GUO Ping, CAI Qi, YANG Mingkang, HUANG Zhixi, XUE Yilun, HUA Renxiang, LIN Han, LI Jiaming, WANG Jianbiao

2025, 40(2): 171-177. DOI: 10.3969/j.issn.1673-8640.2025.02.012

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Objective To analyze the molecular epidemiology of patients with increased stomatocytes and giant platelets in periheral blood. Methods Peripheral blood samples were collected from 30 patients with increased stomatocytes and giant platelets at Ruijin Hospital，Shanghai Jiao Tong University School of Medicine from 2022 to 2023 for whole blood cell count and whole-exome sequencing. The clinical data，basic medical history and sequencing results were collected，the gene mutations of each patient were comprehensively analyzed，and their causes of phenotypic formations were determined. Results Totally，26 patients were accompanied by thrombocytopenia，and 22 patients were accompanied by various degrees of anemia. The sequencing results showed that 8 patients carried mutations in ABCG5 and ABCG8 genes，which were related to phytosterolemia，including 3 homozygous mutations in ABCG5，1 homozygous mutation in ABCG8，2 complex heterozygous mutations in ABCG8 and 2 heterozygous mutations in ABCG5. Totally，5 patients carried heterozygous mutations in PIEZO1 and ABCB6 genes，which were related to hereditary stomatocytosis（HST）. Totally，2 patients carried mutations in LDLR and LDLRAP1 genes，which were related to familial hypercholesterolemia（FH），including 1 heterozygous mutation in LDLR and 1 homozygous mutation in LDLRAP1. Totally，1 patient carried heterozygous mutations in ABCA1 genes，which was related to lipid metabolism. Totally，2 patients carried mutations in SPTA1 and SPTB genes，which were related to hereditary spherocytosis，and one of them carried mutations in both genes simultaneously. Totally，3 patients carried complex heterozygous mutations in RASGRP2，TUBB1 and MYH9 genes，which were related to platelet function，and 2 patients carried complex heterozygous mutations in RASGRP2 and TUBB1，respectively. The other 9 patients carried gene mutations that did not conform to the phenotypes. Conclusions Hereditary gene mutations or secondary factors can lead to stomatocytes with giant platelets. When patients have similar morphological changes，it may point to a variety of different diseases. Timely gene screening and comprehensive analysis of the possible pathogeny are needed.

Changes and clinical value of blood coagulation indexes in children with infection

WANG Chengyun, GU Ping, PAN Qiuhui, WANG Jing

2025, 40(2): 178-181. DOI: 10.3969/j.issn.1673-8640.2025.02.013

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Objective To analyze the changes and clinical value of blood coagulation indexes in infected children with different primary diseases. Methods From January 2021 to December 2022，3 932 infected children（infected group） and 3 932 uninfected children with corresponding primary diseases（uninfected group） were enrolled from Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine，and 3 932 healthy children （healthy control group）were enrolled for coagulation function determination. The difference of relevant indexes between infected group and healthy control group was compared. Results Compared with healthy control group，prothrombin time（PT），activated partial thromboplastin time（APTT） and thrombin time（TT） were prolonged，fibrin/fibrinogen degradation product（FDP） and D-dimer（DD） were increased，and antithrombin-Ⅲ（AT-Ⅲ） activity was decreased in infected group（P<0.05）. There was no statistical significance in fibrinogen（Fib）（P>0.05）. The levels of PT，APTT，TT，Fib，FDP and DD were different in children infected with diseases of cardiovascular system，urinary system，abdominal system and blood system. AT-Ⅲ activity was decreased after infection in children with hematological diseases（P<0.05）. AT-Ⅲ activity in children with severe pneumonia was lower than that in children without severe pneumonia（P<0.05）. Conclusions Blood coagulation indexes have certain value for the diagnosis of infection in children，and the infection status of children with different diseases can be monitored according to the relevant blood coagulation indexes.

Influence of concomitant gene mutation on acute myeloid leukemia patients with RUNX1::RUNX1T1 fusion

TANG Jiemei, WANG Binbin, LIU Na, TANG Gusheng

2025, 40(2): 186-191. DOI: 10.3969/j.issn.1673-8640.2025.02.015

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Acute myeloid leukemia（AML） with RUNX1::RUNX1T1 fusion is a common type of leukemia with unique clinical characteristics. Despite the good remission rates initially achieved with induction therapy，the recent studies have revealed significant heterogeneity in the prognosis of these patients. Particularly when AML with RUNX1::RUNX1T1 fusion is accompanied by other gene mutations，different mutations can influence the development and prognosis of the disease through various mechanisms. The presence of most gene mutations increases the relapse rate and decreases the long-term survival of these patient，which severely impacts their prognosis. This review summarizes the latest research progress on how different gene mutations affect the pathogenesis and prognosis of AML with RUNX1::RUNX1T1 fusion through various mechanisms.

Mechanisms of cancer-associated thrombosis

LI Bo, XIA Yongquan, SHEN Ping, XIA Mao, ZENG Jiawei

2025, 40(2): 192-196. DOI: 10.3969/j.issn.1673-8640.2025.02.016

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Malignant tumors are related to thrombosis，and cancer-associated thrombosisis mainly manifested as spontaneous intra-vascular coagulation activation. At present，thrombosis and its related complications have become the second leading cause of death in cancer patients，after the tumor itself. The mechanism of thrombosis in malignant tumors is complex，and there are differences among patients with different tumors and different stages of malignant tumor progression，which may be related to blood hypercoagulability，vascular wall injury and blood stasis. The 3 elements of thrombosis，namely abnormal blood flow，impaired vascular integrity and changes in blood composition，are all related to the high tendency of thrombosis in tumor patients. Some tumor diagnosis and treatment methods can also increase the occurrence of cancer-associated thrombosis. The risk of venous thromboembolism （VTE） can be increased several times in patients with tumors who have inherited or acquired thromboembolism factors. This review describes the main known mechanisms of cancer-associated thrombosis.

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