TARGETED WHOLE GENOME SEQUENCING FOR DIAGNOSIS IN ADULTS WITH CHRONIC KIDNEY DISEASE OF UNEXPLAINED CAUSE – A HONG KONG COHORT

 

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TARGETED WHOLE GENOME SEQUENCING FOR DIAGNOSIS IN ADULTS WITH CHRONIC KIDNEY DISEASE OF UNEXPLAINED CAUSE – A HONG KONG COHORT

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Becky Mingyao
Ma
Becky Mingyao Ma beckymma@hku.hk Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong Department of Medicine Hong Kong Hong Kong, China *
Shirley Pik Ying Hue spyhue@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Wei Ma weima@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Jamie Sui Lam Kwok jslkwok@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Amy Hin Yan Tong ahytong@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Dingge Ying jdying@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Desiree Man Sik Tse Tse dmstse@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Annie Tsz Wai Chu atwchu@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Desmond Yat Hin Yap Yap desmondy@hku.hk Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong Department of Medicine Hong Kong Hong Kong, China -
Nora Franceschini noraf@unc.edu Gillings School of Global Public Health and School of Medicine, University of North Carolina Departments of Epidemiology and Genetics Chapel Hill, NC United States -
Brian Hon Yin Chung bhychung@genomics.org.hk Hong Kong Genome Institute; School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong Department of Paediatrics and Adolescent Medicine Hong Kong Hong Kong, China -
Su Vui Lo losv@genomics.org.hk Hong Kong Genome Institute Hong Kong Genome Institute Hong Kong Hong Kong, China -
Tak Mao Chan dtmchan@hku.hk Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong Department of Medicine Hong Kong Hong Kong, China -
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Chronic kidney disease of unexplained cause (CKDx) contributes to over 7% of all end stage kidney disease patients on renal replacement therapy in Hong Kong. Overseas cohorts showed that a significant proportion of CKDx are due to genetic etiology. The clinical utility of genetic testing in Chinese CKDx patients remains unclear. 

We prospectively recruited adult CKDx patients from Oct 1 2022 to June 1 2024. CKDx is defined as CKD without a specific cause after standard-of-care diagnostic workup including laboratory and imaging, with or without kidney biopsy. Patients with apparent cause of CKD or those who cannot provide informed consent were excluded. After genetic counselling, patients underwent targeted whole genome sequencing (WGS) focused on kidney disease genes consisting of 637 genes. Variants classification was performed according to the American College of Medical Genetics guidelines.   

A total of 131 CKDx patients were included, with 92% self-identifying as Chinese (Table 1), amongst whom 21% presented with ESKD. Mean age at presentation was 35 years. 36% had positive family history of CKD. We identified Pathogenic/ Likely pathogenic variants in 13 patients, giving a diagnostic yield of 10%. 33% of these variants identified were novel (not included in ClinVar). Variants in type IV collagen genes were the most frequent (COL4A3, COL4A5, COL4A4), followed by ALG9, CEP290 and IFT140 (Figure 1, Table 2). Alport syndrome was the leading genetic diagnosis of CKDx, representing 77% of all genetically tested positive cases. The remaining cases included atypical Autosomal Dominant Polycystic Kidney Disease (ADPKD) and nephronophthisis. Positive genetic testing result was associated with a positive family history of CKD or CKDx (CKD: 85% versus 31%, p<0.001; CKDx: 77% versus 19%, p<0.001)(Table 3).

Table 1. Demographics of study participants.

Entire cohort (n=131)

Age at clinical presentation (mean + SD)

35 ± 13

Age at recruitment (mean + SD)

48 ± 14

Gender

-       Male

-       Female

 

74 (56%)

57 (44%)

Self-declared ethnicity

-       Chinese

-       Non-Chinese

 

120 (92%)

11 (8%)

ESKD at clinical presentation Ϯ

24/117 (21%)

Kidney biopsy ever performed Ϯ

27/118 (23%)

Family history of kidney disease

47 (36%)

Family history of CKDx

32 (24%)

History of nephrotoxic exposure

21 (16%)

Ϯ The denominators for calculation are based on available information retrieved from the electronic health record or collected from the participants.  


Figure 1. Positive genetic testing results. The inner circle represents the disease category. The outer circle represents the genes with pathogenic/ likely pathogenic variants identified. The numbers in brackets represent the number of patients with pathogenic/ likely pathogenic variants identified.


Table 2. Clinical data and genetic variants of patients with positive genetic findings. ACMG, American College of Medical Genetics; CKDx, chronic kidney disease of unexplained cause; Dx, diagnosis; FHx, family history; H, microscopic hematuria; LP, Likely pathogenic; N/A, not available; P, Pathogenic; UP, proteinuria; +, at or above laboratory detection limit; -, below laboratory detection limit.   

 

Gender

Ethnicity

Age at Dx

CKD stage at Dx

Urinalysis

Imaging

Kidney biopsy

Extra-renal manifestation

FHx of CKDx

Variants with

ACMG classification

Novel variant

1

M

Chinese

60

1

H-, UP-

Bilateral kidney cysts, normal sized kidneys

Not performed as not indicated

No

Yes

ALG9:c.427C>T, p.Arg143Ter, NM_024740.2

LP (PVS1, PM2_Supporting)

Yes

2

M

Chinese

66

2

H-, UP-

Bilateral kidney cysts, normal sized kidneys

Not performed as not indicated

No

No

IFT140:c.1035_1036del, p.Gly346AlafsTer137, NM_014714.4

LP (PVS1, PM2_Supporting)

Yes

3

M

Chinese

36

2

H+, UP-

Normal sized kidneys, simple kidney cysts

Thinned glomerular basement membrane in some regions

Bilateral sensorineural hearing loss

No

COL4A3:c.3620G>A, p.Gly1207Glu, NM_000091.5

P (PM2_Supporting, PP3_Strong, PP1_Moderate, PM1)

No

4

F

Chinese

25

5

N/A, UP+

Renal parenchymal disease

Not performed due to advanced CKD

No

Yes

COL4A3:c.2675G>C, p.Gly892Ala, NM_000091.5

LP (PM2_Supporting, PP3_Moderate, PM1, PP1_Moderate)

Yes

5

F

Chinese

39

1

H+, UP+

Normal sized kidneys, simple kidney cysts

Chronic glomerulonephritis

Bilateral sensorineural hearing loss

Yes

COL4A3:c.3643C>T, p.Arg1215Ter, NM_000091.5

P (PVS1, PM2_Supporting, PM3);

COL4A3:c.4793T>G, p.Leu1598Arg, NM_000091.5

P (PM2_Supporting, PP3_Strong, PM3_Very Strong)

No; No

6

F

Filipino

28

5

H+, UP+

Hypoplastic left kidney, right kidney has increased echogenicity

Not performed due to advanced CKD

No

Yes

COL4A5:c.1120G>A, p.Gly374Arg, NM_033380.3

P (PM2_Supporting, PP3_Strong, PM1, PS4_Moderate)

No

7

F

Chinese

25

5

H-, UP+

Renal parenchymal changes

Not performed due to advanced CKD

Retinitis pigmentosa

No

CEP290:c.6439G>T, p.Glu2147Ter, NM_025114.4

LP (PM2_Supporting, PVS1);

CEP290:c.2569A>T, p.Lys857Ter, NM_025114.4

LP (PM2_Supporting, PVS1)

No; No

8

M

Chinese

23

2

H+, UP+

No abnormalities detected

Hypertensive nephrosclerosis, focal segmental glomerulosclerosis

No

Yes

COL4A5:c.1844G>C, p.Gly615Ala, NM_033380.3

LP (PM2_Supporting, PP3_Strong, PM1)

Yes

9

M

Chinese

18

1

H+, UP+

No abnormalities detected

No definite pathological diagnosis

No

Yes

COL4A5:c.475G>A, p.Gly159Ser, NM_033380.3

LP (PM2_Supporting, PP3_Moderate, PM1, PP4)

Yes

10

F

Chinese

33

2

H+, UP+

Increased renal parenchymal echogenicity

Focal segmental glomerulosclerosis, increased variation in glomerular basement membrane thickness

No

Yes

COL4A4:c.2726G>A, p.Gly909Glu, NM_000092.5

P (PM2_Supporting, PP3_Strong, PS4_Supporting, PM1, PP1_Moderate)

No

11

F

Chinese

34

5

H+, UP+

Renal parenchymal changes

Hypertensive nephrosclerosis

No

Yes

COL4A3:c.4486C>T, p.Arg1496Ter, NM_000091.5

P (PVS1, PM2_Supporting, PS4_Supporting)

No

12

F

Chinese

48

1

H+, UP+

Normal sized kidneys, simple kidney cysts

Not performed as good proteinuric control with renin angiotensin system blockade

No

Yes

COL4A3:c.4793T>G, p.Leu1598Arg, NM_000091.5

P (PM2_Supporting, PP3_Strong, PM3_Very Strong)

No

13

M

Chinese

58

4

H-, UP+

Renal parenchymal changes

Not performed as advanced CKD

Bilateral sensorineural hearing loss

Yes

COL4A4:c.2726G>A, p.Gly909Glu, NM_000092.5

P (PM2_Supporting, PP3_Strong, PS4_Supporting, PM1, PP1_Moderate)

No

Table 3. Predictors of a positive genetic finding. CKDx, chronic kidney disease of unexplained cause. ESKD, end stage kidney disease. SD, standard deviation.  

Positive genetic findings (n=13)

Negative genetic findings (n=118)

p-value

Age at clinical presentation (mean + SD)

38 ± 15

35 ± 13

0.463

Age at recruitment (mean + SD)

50 ± 16

47 ± 14

0.542

Gender

-       Male

-       Female

 

6 (46%)

7 (54%)

 

68 (58%)

50 (42%)

 

0.428

Self-declared ethnicity

-       Chinese

-       Non-Chinese

 

12 (92%)

1 (8%)

 

108 (92%)

10 (8%)

 

0.971

ESKD at clinical presentation Ϯ

4/13 (31%)

20/104 (19%)

0.331

Kidney biopsy ever performed Ϯ

6/13 (46%)

21/105 (20%)

0.039

Family history of kidney disease Ϯ

11/13 (85%)

36/118 (31%)

<0.001

Family history of CKDx Ϯ

10/13 (77%)

22/118 (19%)

<0.001

History of nephrotoxic exposure Ϯ

1/13 (8%)

20/118 (17%)

0.388

Ϯ The denominators for calculation are based on available information retrieved from the electronic health record or collected from the participants.  

We showed that a diagnosis of genetic kidney disease could be established in 10% of adult patients with CKDx in Hong Kong Chinese. Collagenopathies such as Alport Syndrome is the leading genetic diagnosis, followed by atypical ADPKD and nephronophthisis. Testing for genetic kidney diseases in CKDx is useful in clinical management, since a significant proportion could reach a diagnosis and permit disease specific management. 

Kewords