search for


Importance of family segregation in the American College of Medical Genetics and Genomics and Association of Molecular Pathology guidelines: Case of a Korean family with autosomal dominant polycystic disease
Journal of Genetic Medicine 2020;17:51-54
Published online June 30, 2020;
© 2020 Korean Society of Medical Genetics and Genomics.

Won Kyung Kwon1, Suhee Kim2, Ja-Hyun Jang1, and Jong-Won Kim1,*

1Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Outpatient Nursing Team, Samsung Medical Center, Seoul, Korea
Jong-Won Kim, M.D., Ph.D.
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.
Tel: +82-2-3410-2705, Fax: +82-2-3410-2719, E-mail:
Received May 19, 2020; Revised June 16, 2020; Accepted June 17, 2020.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Since the American College of Medical Genetics and Genomics and Association of Molecular Pathology published their guidelines in 2015, most interpretations of genetic tests have followed them. However, all variants have only limited evidence along 28 interpretation standards, especially de novo variants. When de novo variants, which are classified as variants of uncertain significance (VUS) due to lack of evidence, are detected, segregation in the affected family could provide an important key to clarifying the variants. Autosomal dominant polycystic kidney disease is the most common inherited kidney disorder with pathogenic variants in the PKD1 or PKD2 genes. We detected a novel in-frame deletion variant in the PKD1 gene, c.7575_7577del (p.(Cys2526del)), which was interpreted as a VUS. We analyzed this variant in a Korean family to decide for segregation. Here, we report the variant as a likely pathogenic variant based on the evidence of segregation in three affected relatives and two unaffected members.
Keywords : Autosomal dominant, Polycystic kidney, Polycystic kidney disease 1 protein.

The American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) published their guidelines in 2015 to help improve and standardize the pathogenicity classification of genomic variants [1]. The ACMG-AMP classification guidelines offer eight categories, each of which can provide support for the classification of a variant as benign (BV), likely benign (LBV), variant of uncertain significance (VUS), likely pathogenic (LPV), or pathogenic (PV). However, most variants do not have all the evidence and are interpreted based on only limited known evidence. In this context, de novo variants are easily classified as VUS because they have very limited category evidence. When interpreting these novel variants, segregation data could be important to clarifying the classification.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, occurring at a frequency of 1 in 400 to 1 in 1,000 individuals among different populations [2]. ADPKD is a systemic disease that involves several organs including the kidney, liver, pancreas, and cardiovascular organs [2-5], and leads to end-stage renal disease (ESRD). This disease is caused by PV in the PKD1 (Online Mendelian Inheritance in Man [OMIM] no. 601313) and PKD2 (OMIM no. 173910) genes, but 85% to 90% of ADPKD cases are caused primarily by mutations in the PKD1 gene [6].

Diagnosis of ADPKD is mainly based on renal imaging studies such as renal ultrasound, magnetic resonance imaging, and computed tomography (CT) using the age-related cyst number criteria [7,8]. However, because genetic diagnosis is definitive, clinicians try to detect the PV in the PKD1 or PKD2 genes. Additionally, the detection of variants before appearance of symptoms in at-risk families would help carriers get timeous clinical care. This trial is extended to the prenatal diagnosis and preimplantation genetic diagnosis (PGD). Therefore, defining the comprehensive mutation of the PKD1/PKD2 genes is the key to early diagnosis of ADPKD and early genetic intervention.

In this report, we identified an in-frame deletion variant, which has never been reported, as an LPV in a Korean family segregation study.


A 31-year-old woman visited our genetic counseling center for pregnancy consultation. She had no obstetrical history and wanted to have a baby. She and her mother have multiple cysts of the kidney, which were diagnosed as polycystic kidney disease (PKD) based on a CT image study. She wanted to try for PGD. However, they had never taken a genetic test, which is necessary for PGD. Therefore, we tested them by Sanger sequencing of the PKD1 and PKD2 genes. Both patients did not present any pathogenic/LPV of the PKD2 gene. However, in the PKD1 gene, a heterozygous 3-base-pair deletion, c.7575_7577del, was detected in exon 19: NM_001009944.2:c.7575_7577del, p.(Cys2526del). This variant was classified as VUS using the ACMG/AMP guidelines [1]. The evidence was that there was no reported allele frequency on population databases (PM2) and protein length change (PM4) (Table 1). Based on this evidence, we could not diagnose her and her mother with ADPKD by a genetic test. However, she has a more affected uncle, an elder brother of her mother (II-2 in Fig. 1). He has a result of polycystic disease on both kidneys and liver by ultrasonography. Therefore, we suggested that she visit the genetic counseling clinic with him, another unaffected uncle (II-3), and her younger sister (III-2). Eventually, we were faced with a Korean family of five members (three affected and two unaffected) with a family history of ADPKD, and had to confirm whether the variant exists or not (Fig. 1). The results were interesting. All affected patients—the proband (III-1), mother (II-4), and elder uncle with PKD (II-2)—who were diagnosed with PKD using imaging studies and clinical symptoms, had the same heterozygote variant. Moreover, the unaffected family members—her sister (III-2) and the unaffected uncle (II-4) —whose CT images were normal, did not have the variant (Fig. 2). Before this family study was conducted, in-frame deletion variant (PKD1: c.7575_7577del) was interpreted as VUS because of limited evidence. However, after studying this family, we had more evidence including a highly specific phenotype (PP4) and co-segregation with multiple affected members (PP1) (Table 1). Finally, there were two moderate evidence of pathogenicity and two supporting evidence of pathogenicity, which were used to revise the interpretation as LPV. After studying this variant for segregation, the patient could have a medical record for PGD.


ADPKD is the most common inherited kidney disorder. This disease is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and increased risk of intracranial aneurysms [3,4]. Although a diagnosis is primarily based on clinical suggestive findings such as multiple bilateral renal cysts, intracranial aneurysm, family history of ADPKD, and age-specific imaging findings, genetic tests should be performed for genetic counseling. Updating and reporting the PV of the PKD1 and PKD2 genes could help other geneticists interpret their variants. The PKD1 gene consists of 46 exons and the PKD2 gene consists of 15 exons. To date (06/04/2020), a total of 2,323 variants in the PKD1 gene and 278 variants in the PKD2 gene have been reported in the Polycystic Kidney Disease Mutation Database (PKDB; The data are continuously updated with every report, usually based on a single-family entity.

Co-segregation of the disease in multiple affected family members was considered supporting evidence of pathogenicity in the ACMG-AMP guidelines, and increased segregation data were considered moderate or strong evidence of pathogenicity. Moreover, Bayrak-Toydemir et al. [9] proposed the Bayes factor (BF) method that computes a likelihood ratio for quantitation of evidence. Novel variants, which could be classified as VUS due to lack of a previous report, in-silico prediction, and allele frequencies, need more evidence to support them. We report a study in an affected family. The variant (PKD1: c.7575_7577del) in our case is counted as VUS at best because we assigned only PM2 and PM4 evidence. Clingen and his working group explained it using specific numbers of affected members [10]. The study of the trio (proband and biological parents) is not enough to provide the evidence or score for LPV to this variant. A large extended family segregation study enabled the addition of PP1 and PP4 to this variant and the PKD1: c.7575_7577del variant to become LPV. In the case of the novel variants, our case shows that large extended family segregation study could solve the VUS issue, and indicates the importance of the large extended family segregation study if available.

With diagnosis by clinical features, genetic diagnosis becomes important. In this context, counseling becomes more important than before. Generally, a VUS should not be used in clinical decision-making, but clinical findings and family history should also be taken into account [11]. In addition, some VUS could be reclassified as pathogenic because of the patient’s specific phenotype and segregation studies. These reclassifications may have an important impact on genetic counseling. By this step, we could build trust between genetic counselors and patients.

Fig. 1. Pedigree of autosomal dominant polycystic kidney disease (ADPKD) patient. We tested proband (III-1) and the members (II-2, 3, 4, and III-2).
Fig. 2. The results of Sanger sequencing. The upper three patients (III-1, II-2 and II-4) had the variants. Only forward sequencings were showed.

Criteria for classifying pathogenic variants for this case

Evidence Description In this case
PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium Absent from controls
PM4 Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants In-frame deletions (an amino acid)
PP1_Supporting Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
Note: May be used as stronger evidence with increasing segregation data Cosegregation with mother, proband and uncle with unaffected members (another uncel and sister).
PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology Kidney cysts

PM, pathogenic moderate; PP, pathogenic supporting.

  1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.
    Pubmed KoreaMed CrossRef
  2. Simms RJ. Autosomal dominant polycystic kidney disease. BMJ 2016;352:i679.
    Pubmed CrossRef
  3. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-64.
    Pubmed CrossRef
  4. Srivastava A, Patel N. Autosomal dominant polycystic kidney disease. Am Fam Physician 2014;90:303-7.
  5. Lai S, Mastroluca D, Matino S, Panebianco V, Vitarelli A, Capotosto L, et al. Early markers of cardiovascular risk in autosomal dominant polycystic kidney disease. Kidney Blood Press Res 2017;42:1290-302.
    Pubmed CrossRef
  6. Kurashige M, Hanaoka K, Imamura M, Udagawa T, Kawaguchi Y, Hasegawa T, et al. A comprehensive search for mutations in the PKD1 and PKD2 in Japanese subjects with autosomal dominant polycystic kidney disease. Clin Genet 2015;87:266-72.
    Pubmed CrossRef
  7. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994;343:824-7.
    Pubmed CrossRef
  8. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, et al; CRISP Investigators. Volume progression in polycystic kidney disease. N Engl J Med 2006;354:2122-30.
    Pubmed CrossRef
  9. Bayrak-Toydemir P, McDonald J, Mao R, Phansalkar A, Gedge F, Robles J, et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol 2008;85:45-9.
    Pubmed CrossRef
  10. The Clinical Genome Resource Gene Curation Working Group. Gene clinical validity curation process: standard operating procedure. Version 7.
  11. Elliott AM, Friedman JM. The importance of genetic counselling in genome-wide sequencing. Nat Rev Genet 2018;19:735-6.
    Pubmed CrossRef

June 2020, 17 (1)
Full Text(PDF) Free

Social Network Service

Cited By Articles
  • CrossRef (0)

Author ORCID Information