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Carrier burden of over 300 diseases in Han Chinese identified by expanded carrier testing of 300 couples using assisted reproductive technology

  • Assisted Reproduction Technologies
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Abstract

Background

Expanded carrier screening (ECS) has become a common practice for identifying carriers of monogenic diseases. However, existing large gene panels are not well-tailored to Chinese populations. In this study, ECS testing for pathogenic variants of both single-nucleotide variants (SNVs) and copy number variants (CNVs) in 330 genes implicated in 342 autosomal recessive (AR) or X-linked diseases was carried out. We assessed the differences in allele frequencies specific to the Chinese population who have used assisted reproductive technology (ART) and the important genes to screen for in this population.

Methodology

A total of 300 heterosexual couples were screened by our ECS panel using next-generation sequencing. A customed bioinformatic algorithm was used to analyze SNVs and CNVs. Guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology were adapted for variant interpretation. Pathogenic or likely pathogenic (P/LP) SNVs located in high homology regions/deletions and duplications of one or more exons in length were independently verified with other methods.

Results

64.83% of the patients were identified to be carriers of at least one of 342 hereditary conditions. We identified 622 P/LP variants, 4.18% of which were flagged as CNVs. The rate of at-risk couples was 3%. A total of 149 AR diseases accounted for 64.05% of the cumulative carrier rate, and 48 diseases had a carrier rate above 1/200 in the test.

Conclusion

An expanded screening of inherited diseases by incorporating different variant types, especially CNVs, has the potential to reduce the occurrence of severe monogenic diseases in the offspring of patients using ART in China.

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Data availability

We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.

Abbreviations

21-OHD:

21-hydroxylase deficiency

ABCC8:

ATP binding cassette subfamily C member 8

ACMG:

the American College of Medical Genetics

ACOG:

the American College of Obstetricians and Gynecologists

ALMS1:

ALMS1 centrosome and basal body–associated protein

AMP:

association for molecular pathology

APOB:

apolipoprotein B

AR:

autosomal recessive

ARCs:

sat-risk couples

ARSA:

arylsulfatase A

ART:

assisted reproductive technology

ASPA:

aspartoacylase

ATP7B:

ATPase copper transporting beta

BRCA2:

BRCA2 DNA repair associated

CAH:

congenital adrenal hyperplasia

CCR:

cumulative carrier rate

CCR:

cumulative carrier rate

CDH23:

cadherin related 23

CF:

carrier frequency

CF:

cystic fibrosis

CFTR:

CF transmembrane conductance regulator

CNVs:

copy number variants

CS:

carrier screening

CYP21A2:

cytochrome P450 family 21 subfamily A member 2

DCLRE1C:

DNA cross-link repair 1C

DNAH5:

dynein axonemal heavy chain 5

DSP:

desmoplakin

ECS:

expanded carrier screening

EDTA:

ethylene diamine tetraacetic acid

ERCC8:

ERCC excision repair 8, CSA ubiquitin ligase complex subunit

EYS:

eyes shut homolog

F11:

coagulation factor XI

F8:

coagulation factor VIII

G2P:

gene-to-pseudogene ratio

G6PD:

glucose-6-phosphate dehydrogenase

GALT:

galactose-1-phosphate uridylyltransferase

GCR:

gene carrier rate

GJB2:

gap junction protein beta 2

GSNs:

gene-specific nucleotides

HBA1/HBA2:

hemoglobin subunit alpha 1/hemoglobin subunit alpha 2

HBB:

hemoglobin subunit beta

HFE:

homeostatic iron regulator

Indels:

small insertions and deletions

IVF:

sodium voltage-gated channel alpha subunit 5

KCNQ1:

potassium voltage-gated channel subfamily Q member 1

LDLR:

low density lipoprotein receptor

LIPA:

lipase A, lysosomal acid type

LMNA:

lamin A/C

LR-PCR:

long-range polymerase chain reaction

MI:

misalignment index

MLPA:

multiplex ligation–dependent probe amplification

MMA-HCU:

methylmalonic acidemia with homocystinuria

MSH2:

mutS homolog 2

MTHFR:

methylenetetrahydrofolate reductase

NC:

nonclassic

NCBI:

National Center for Biotechnology Information

NEB:

nebulin

NGS:

the next-generation sequencing

NHC:

the National Health Commission of the People’s Republic of China

NIH:

the National Institutes of Health

NPHP1:

nephrocystin 1

NPV:

negative predictive value

OMIM:

Online Mendelian Inheritance in Man

OTC:

ornithine transcarbamylase

P/LP:

pathogenic or likely pathogenic

PKHD1:

PKHD1 ciliary IPT domain containing fibrocystin/polyductin

PKP2:

plakophilin 2

PMS2:

PMS1 homolog 2, mismatch repair system component

PPV:

positive predictive value

qPCR:

quantitative polymerase chain reaction

RB1:

RB transcriptional corepressor 1

RET:

ret proto-oncogene

SARCs:

suspected sat-risk couples

SDHC:

succinate dehydrogenase complex subunit C

SLC22A5:

solute carrier family 22 member 5

SLC25A13:

solute carrier family 25 member 13

SLC25A13:

solute carrier family 25 member 13

SLC26A4:

solute carrier family 26 member 4

SLC4A11:

solute carrier family 4 member 11

SLC7A7:

solute carrier family 7 member 7

SMA:

spinal muscular atrophy

SMAD3:

SMAD family member 3

SMAD4:

SMAD family member 4

SMN1:

survival of motor neuron 1, telomeric

SNVs:

single-nucleotide variants

STR:

short tandem repeat

SV:

simple virilizing

SW:

salt wasting

TSC2:

TSC complex subunit 2

TSD:

Tay-Sachs disease

TTC37:

tetratricopeptide repeat domain 37

UGT1A1:

UDP glucuronosyltransferase family 1 member A1

USH1C:

USH1 protein network component harmonin

USH2A:

usherin

VCR:

variant carrier rate

VUS:

variant uncertain significance

WNT10A:

Wnt family member 10A

WNT10A:

Wnt family member 10A

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Acknowledgements

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Funding

This work was supported by the research grant from the sub-project of the National Key R&D Program (2021YFC2701002, 2022YFC2703702), National Natural Science Foundation of China (Nos. 81971344, 82171677, 82192864, 82088102 and 81901495), the Shanghai Municipal Commission of Science and Technology Program (22S31901500, 23ZR1408000, 21Y21901002), Shanghai Municipal Commission of Health and family planning (202140110), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5-064), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), Clinical Research Plan of SHDC (SHDC2020CR1008A), Shanghai Clinical Research Center for Gynecological Diseases (22MC1940200), Shanghai Urogenital System Diseases Research Center (2022ZZ01012) and Shanghai Frontiers Science Research Center of Reproduction and Development.

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Author notes

  1. Song-Chang Chen and Xuan-You Zhou contributed equally to this work.

Authors and Affiliations

  1. Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, 566 Fangxie Road, Huangpu District, Shanghai, 200001, China

    Song-Chang Chen, Xuan-You Zhou, He-Feng Huang & Chen-Ming Xu

  2. International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China

    Song-Chang Chen, Xuan-You Zhou, Shu-Yuan Li, He-Feng Huang & Chen-Ming Xu

  3. Fujungenetics Biotechnology Co., Ltd., No. 70 of Tongchuan Road, Putuo District, Shanghai, 200333, China

    Ming-Min Zhao & Jia Jia

  4. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences (No. 2019RU056), Shanghai, China

    He-Feng Huang

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Contributions

Conception and design of the research: SCC, CMX, JJ, HFH

Acquisition of data: XYZ, SYL

Analysis and interpretation of the data: JJ, XYZ

Statistical analysis: JJ, SCC

Obtaining financing: SCC, CMX, HFH

Writing of the manuscript: JJ, MMZ

Critical revision of the manuscript for intellectual content: SCC, CMX, XYZ

All authors read and approved the final draft.

Corresponding authors

Correspondence to Jia Jia or Chen-Ming Xu.

Ethics declarations

Ethics approval and consent to participate

This study was conducted with approval from the Ethics Committee of Obstetrics and Gynecology Hospital Affiliated to Fudan University (No: 2021-28), and registered in the Chinese Clinical Trial Register website (www.chictr.org.cn, ChiCTR2100050723). Written informed consent was obtained from all participants.

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All participants signed a document of informed consent.

Competing interests

Authors Ming-Min Zhao and Jia Jia are employed by Fulgent Technologies Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Chen, SC., Zhou, XY., Li, SY. et al. Carrier burden of over 300 diseases in Han Chinese identified by expanded carrier testing of 300 couples using assisted reproductive technology. J Assist Reprod Genet 40, 2157–2173 (2023). https://doi.org/10.1007/s10815-023-02876-y

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