Navigating the landscape of clinical genetic testing: insights and challenges in rare disease diagnostics

Soo Yeon Kim Korean Society of Pediatric Nephrology 2024 Childhood kidney diseases Vol.28 No.1

With the rapid evolution of diagnostic tools, particularly next-generation sequencing, the identification of genetic diseases, predominantly those with pediatric-onset, has significantly advanced. However, this progress presents challenges that span from selecting appropriate tests to the final interpretation of results. This review examines various genetic testing methodologies, each with specific indications and characteristics, emphasizing the importance of selecting the appropriate genetic test in clinical practice, taking into account factors like detection range, cost, turnaround time, and specificity of the clinical diagnosis. Interpretation of variants has become more challenging, often requiring further validation and significant resource allocation. Laboratories primarily classify variants based on the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science guidelines, however, this process has limitations. This review underscores the critical role of clinicians in matching patient phenotypes with reported genes/variants and considering additional factors such as variable expressivity, disease pleiotropy, and incomplete penetrance. These considerations should be aligned with specific gene-disease characteristics and segregation results based on an extended pedigree. In conclusion, this review aims to enhance understanding of the complexities of clinical genetic testing, advocating for a multidisciplinary approach to ensure accurate diagnosis and effective management of rare genetic diseases.

Clinical Manifestation Patterns and Trends in Poststreptococcal Glomerulonephritis

Kim, Kee Hyuck Korean Society of Pediatric Nephrology 2016 Childhood kidney diseases Vol.20 No.1

Poststreptococcal glomerulonephritis (PSGN) is one of the most recognized diseases in pediatric nephrology. Typical clinical features include rapid onset of gross hematuria, edema, and hypertension, and cases are typically preceded by an episode of group A ${\beta}$-hemolytic streptococcus pharyngitis or pyoderma. The most common presenting symptoms of PSGN are the classic triad of glomerulonephritis: gross hematuria, edema, and hypertension. However, patients with PSGN sometimes present with unusual or atypical clinical symptoms that often lead to delayed diagnosis or misdiagnosis of the disease and increased morbidity. Additionally, the epidemiology of postinfectious glomerulonephritis (PIGN), including PSGN, has changed over the past few decades. This paper reviews atypical clinical manifestations of PSGN and discusses the changing demographics of PIGN with a focus on PSGN.

Experience with Pediatric Kidney Transplantation, 1985-2016: A Single Regional Center Study

Min, So Yoon,Jo, Tae Kyoung,Baek, Hee Sun,Park, Sook-Hyun,Kim, Hyung-Kee,Huh, Seung,Cho, Min Hyun Korean Society of Pediatric Nephrology 2017 Childhood kidney diseases Vol.21 No.2

Purpose: Kidney transplantation (KT) is an ideal treatment for pediatric patients with end-stage renal disease (ESRD). We report the clinical outcomes of pediatric ESRD patients who underwent KT in a single regional center. Methods: We retrospectively investigated the medical records of 60 pediatric patients who were diagnosed with ESRD and underwent KT in our hospital between January 1985 and June 2016. Results: A total of 60 children and adolescents (40 male, 20 female; mean age, $13.86{\pm}4.26$ years) were included in this study. Six patients (10.0%) underwent KT immediately after receiving the diagnosis of ESRD, while the others underwent KT after dialysis treatment (mean period of dialysis, $368.7{\pm}4,41.8$ days). The mean donor age (50 living-related [83.3%], 10 deceased [16.7%]) was $40.0{\pm}12.85$ years and the male:female ratio was 1.07:1. The most common cause of ESRD was chronic glomerulonephritis. The overall survival rates at 1, 3, and 5 years after KT were 98%, 98%, and 96%, respectively, while the graft survival rates at 1, 3, and 5 years were 93%, 86%, and 68%, respectively. Children who underwent KT before 10 years of age had better monthly growth rates than those who underwent KT later than 10 years of age. Conclusions: KT is performed less frequently in children than in adults, but causes of ESRD vary and clinical outcomes after KT greatly affect the growth and development of pediatric patients. Therefore, further analysis and monitoring of clinical progression after KT in pediatric ESRD patients are necessary.

Novel SLC5A2 Mutations and Genetic Characterization in Korean Patients with Familial Renal Glucosuria

Lee, Weon Kyung,Oh, Seung Hwan,Chung, Woo Yeong Korean Society of Pediatric Nephrology 2018 Childhood kidney diseases Vol.22 No.2

Purpose: Familial renal glucosuria (FRG, OMIM #233100) is a rare but relatively benign genetic condition characterized by persistent isolated glucosuria with a normal blood glucose level. We report three additional SLC5A2 mutations and examine their phenotypic and genetic characteristics in a Korean FRG cohort. We also reviewed the literature and summarized the genotypes of all Korean patients with FRG. Methods: A genetic analysis was conducted by directly sequencing all 14 exons of the SLC5A2 gene and their flanking regions in six unrelated Korean children with FRG and their family members. Novel non-synonymous single-nucleotide polymorphisms were identified and compared with known mutations that are repeatedly detected in the Korean population. Results: We found two novel mutations [c.274G>A (G92S) and c.1168C>T (L390F)] and one known [c.1382G>A (S461N)] mutation in each family and one recurrent mutation [c.1346G>A (G449D) (rs768392222)] in two pedigrees. The recurrent G449D was predicted to be "possibly damaging," with a score of 0.883 in Polyphen-2, while G92S, L390F, and S461N were predicted to be "probably damaging," with scores of 1.000, 0.999, and 0.996, respectively. Conclusions: Two novel, one previously reported, and one recurrent mutation were identified in six Korean FRG pedigrees as causative mutations of renal glucosuria. Sequence variations in the SLC5A2 gene were frequently detected in children with persistent isolated glucosuria. A long-term follow-up of this FRG cohort is needed to understand how these specific SGLT2 mutations impair kidney function and energy homeostasis.

Analysis of Octyl-2-Cyanoacrylate as a Dressing Material after Pediatric Urological Procedures

이한이,민선호,김광명,Lee, Hahn-Ey,Min, Sun Ho,Kim, Kwang Myung Korean Society of Pediatric Nephrology 2012 Childhood kidney diseases Vol.16 No.2

목적: 소아비뇨기과 관혈적 수술 시 피부봉합제로 사용된 Octyl-2-Cyanoacrylate (Dermabond$^{TM}$)의 효용성에 대해 알아보고자 하였다. 방법: 2010년 8월부터 2011년 8월까지 1년 동안 서울대학교 어린이병원 소아비뇨기과에서 단일 술자에 의해 음낭수종절제술, 고환고정술, 음경성형술을 시행받은 환자들을 대상으로 상처 합병증 발생율을 후향적으로 비교분석하였다. 총 128명을 대상으로 210개의 절개 창에서 시행되었으며, 피부 봉합에 Dermabond$^{TM}$을 사용하였다. 모든 절 개창은 Dermabond$^{TM}$을 사용하기 전 흡수사를 이용하여 표피 밑 봉합 혹은 몇 개의 단순 봉합을 시행하였다. Dermabond$^{TM}$는 4 mm 너비로 얇게 두 번 사용되었으며, 건조시키는 과정이 포함되었다. 추가적인 붕대나 드레싱은 적용되지 않았다. 결과: 128명의 환자들을 수술 종류에 따라 세 그룹으로 나누었다(Group 1: 음낭수종 절제술, 55례, 41.3%; Group 2: 고환고정술, 43례, 32.3%; Group 3: 음경성형술, 35례, 26.4%). 수술 후 외래에서 추적 관찰한 210개의 절개창 중에서 총 5개(2.3%)에서 상처 합병증이 발생하였고, 이를 그룹별로 다시 분석해 보면 Group 1에서 0개(0/55, 0%), Group 2에서 1개(1/43, 2.3%), Group 3에서 4개(4/35, 11.4%)가 각각 발생하였다. 상처 부위별로 다시 분석해 보면 서혜부 상처 1개(1/120, 0.83%), 고환 상처 0개(0/55, 0%), 음경 상처 4개(4/35, 11.4%)가 각각 발생하였다. Group 3의 음경 상처에서 다른 군에 비해 통계적으로 의미 있게 증가되었다(P=0.008). Group 2와 3에서 상처 합병증이 발생한 환자들의 평균 나이는 각각 1세, 9.50세 이었고 상처 합병증이 없는 환자들의 평균 나이는 2.34세, 5.61세 였지만 통계적으로 의미는 없었다(P=0.639, 0.122). 5개의 상처 합병증은 모두 가벼운 염증반응이었으며, 항생제 연고만을 적용 후 술 후 평균 13.8일(13-15일) 후 모두 치료되었다. 결론: Dermabond$^{TM}$는 소아비뇨기과에서 음낭수종절제술과 고환고정술 시 피부봉합제로서 기존의 피부 봉합에 대한 대안으로 안전한 방법으로 사료된다. 하지만 음경성형술에서는 향후 더 많은 연구가 필요하다. Purpose: We aimed to evaluate the efficacy of Octyl-2-cyanoacrylate (Dermabond$^{TM}$) as a topical skin adhesive for pediatric urologic open surgery. Methods: From August 2010 to August 2011, we retrospectively evaluated pediatric patients who underwent urologic open surgery at our institution. A total of 128 pediatric patients with 210 incisions used Dermabond$^{TM}$ for skin closure. Results: We divided the 128 patients into 3 groups according to type of surgery. Group 1 underwent hydrocelectomy (55 cases, 41.3%), Group 2 underwent orchiopexy (43 cases, 32.3%), Group 3 underwent penoplasty (35 cases, 26.4%). One hundred and twenty eight patients who underwent 133 surgeries in total, with a total of 210 incisions visited our outpatient department postoperatively, and a total of 5 wound complications (2.3%) occurred, but were simple inflammations and no dehiscence was observed. When analyzed according to groups, no wound problems occurred in Group 1 (0/55, 0%), one occurred in Group 2 (1/43, 2.3%) and four cases occurred in Group 3 (4/35, 11.4%) respectively. When re-analyzed according to wound locations, one occurred in an inguinal wound (1/120, 0.83%), none occurred in scrotal wounds (0/55, 0%), and four occurred in penile wounds (4/35, 11.4%). In Group 3, the incidence of penile wounds was significantly increased compared to other groups (P=0.008). All 5 wound problems were inflammatory and healed at an average of 13.8 days (13-15 days) with antibiotic ointment application only. Conclusion: Dermabond$^{TM}$ is feasible and safe topical skin adhesive alternative to standard skin suture in pediatric urologic surgery. However, further research about its efficacy and safety could be valuable in the future.

A Long Way from Transfer to Transition: Challenges for Pediatric and Adult Nephrologists

Lemke, Johanna,Pape, Lars,Oh, Jun Korean Society of Pediatric Nephrology 2018 Childhood kidney diseases Vol.22 No.1

Significant advances in the diagnosis and medical care of children with chronic kidney disease (CKD) are major reasons for the better survival rates of children and adolescents with CKD than the survival rates reported in previous decades. These patients are reaching adulthood, and therefore require a transition to adult medical care. This transition phase is well-recognized to be associated with considerably increased morbidities and medical problems, such as non-adherence, graft loss after transplantation, and loss to follow-up. Low adherence increases morbidity and medical complications and contributes to poorer qualities of life and an overuse of the health care system. However, these tragic outcomes may be avoidable through a structured and well-defined transition program. In the last decade, there has been increasing interest to resolve these medical and psychological problems that occur during the transfer of young adult patients from pediatric to adult renal units. The aims of a successful transition from pediatric to adult medical care include enhancing the individual development of better health-competence and stabilizing, or even improving, the state of health. This review will focus on various aspects of the transition phase of adolescents who have CKD or who underwent kidney transplantation from pediatric to adult nephrology care.

Pediatric Kidney Transplantation

Lee, Yeon Hee,Kang, Hee Gyung Korean Society of Pediatric Nephrology 2021 Childhood kidney diseases Vol.25 No.1

Pediatric kidney transplantation is the best option since it can achieve near normal glomerular filtration rate, adequate fluid balance, and autonomic endocrine function of the kidney in end-stage kidney disease. However, pediatric kidney transplantation is difficult because children are developing and growing, management and complications of pediatric kidney transplantation are different from those of adults. This review covers the current status of pediatric kidney transplantation in Korea, key considerations that must be taken before kidney transplantation in children, and management strategy of immunosuppression and common complications.

Malignancy after Pediatric Kidney Transplantation: The 30-Year Experience of a Single Center

Jung, Jiwon,Park, Young Seo,Han, Duck Jong Korean Society of Pediatric Nephrology 2020 Childhood kidney diseases Vol.24 No.2

Objectives: We aimed to investigate the incidence, manifestations, and outcomes of malignancy after pediatric kidney transplantation (KT) at our center over 30 years. Methods: We retrospectively reviewed the medical records of 155 patients under 18 years of age who underwent KT between January 1990 and February 2020 at Asan Medical Center. Results: Twelve patients (7.7%) were diagnosed with a malignancy after KT. Malignancy was diagnosed after a mean period of 6.4±5.9 years (median 4.6, range 0.5-20.6 years) after KT. Nine (75.0%) of the 12 cancer patients were diagnosed with post-transplant lymphoproliferative disease (PTLD), and the other three had papillary thyroid cancer, mucoepidermoid cancer of the hard palate, and T-cell acute lymphoblastic leukemia, respectively. PTLD was diagnosed within a mean of 3.7±3.4 years (median 3.7, range 0.5-9.8 years) after KT. Five patients diagnosed with PTLD were cured without recurrence. Three patients with PTLD died from the disease, and one patient with mucoepidermoid cancer from a non-PTLD malignancy died after progression, despite surgical resection and chemotherapy. Three (33.3%) of the nine survivors progressed to end-stage renal disease (ESRD) after completing cancer treatment. No patient with post-transplant malignancy (PTM) experienced critical renal deterioration during cancer treatment. Conclusion: PTLD was the most common PTM, occurring at 5.8% of the pediatric KT patients after KT in our center. Careful follow up is needed particularly considering the risk of PTLD after KT in children.

Genetic analysis using whole-exome sequencing in pediatric chronic kidney disease: a single center's experience

Lee, Hyeonju,Min, Jeesu,Ahn, Yo Han,Kang, Hee Gyung Korean Society of Pediatric Nephrology 2022 Childhood kidney diseases Vol.26 No.1

Purpose: Chronic kidney disease (CKD) has various underlying causes in children. Identification of the underlying causes of CKD is important. Genetic causes comprise a significant proportion of pediatric CKD cases. Methods: In this study, we performed whole-exome sequencing (WES) to identify genetic causes of pediatric CKD. From January to June 2021, WES was performed using samples from pediatric patients with CKD of unclear etiology. Results: Genetic causes were investigated using WES in 37 patients (17 males) with pediatric CKD stages 1 (n=5), 2 (n=7), 3 (n=2), 4 (n=2), and 5 (n=21). The underlying diseases were focal segmental glomerulosclerosis (n=9), congenital anomalies of the kidney and urinary tract including reflux nephropathy (n=8), other glomerulopathies (n=7), unknown etiology (n=6), and others (n=7). WES identified genetic causes of CKD in 12 of the 37 patients (32.4%). Genetic defects were discovered in the COL4A4 (n=2), WT1 (n=2), ACTN4, CEP290, COL4A3, CUBN, GATA3, LAMA5, NUP107, and PAX2 genes. WT1 defects were found in patients whose pathologic diagnosis was membranoproliferative glomerulonephritis, and identification of CUBN defects led to discontinuation of immunosuppressive agents. Genetic diagnosis confirmed the clinical diagnosis of hypoparathyroidism, sensorineural deafness, and renal disease; Alport syndrome; and Joubert syndrome in three of the patients with CKD of unknown etiology (COL4A4 [n=2], CUBN [n=1]). Extrarenal symptoms were considered phenotypic presentations of WT1, PAX2, and CEP290 defects. Conclusions: WES provided a genetic diagnosis that confirmed the clinical diagnosis in a significant proportion (32.4%) of patients with pediatric CKD.

Clinical Guideline for Childhood Urinary Tract Infection (Second Revision)

Lee, Seung Joo Korean Society of Pediatric Nephrology 2015 Childhood kidney diseases Vol.19 No.2

To revise the clinical guideline for childhood urinary tract infections (UTIs) of the Korean Society of Pediatric Nephrology (2007), the recently updated guidelines and new data were reviewed. The major revisions are as follows. In diagnosis, the criterion for a positive culture of the catheterized or suprapubic aspirated urine is reduced to 50,000 colony forming uits (CFUs)/mL from 100,000 CFU/mL. Diagnosis is more confirmatory if the urinalysis is abnormal. In treating febrile UTI and pyelonephritis, oral antibiotics is considered to be as effective as parenteral antibiotics. In urologic imaging studies, the traditional aggressive approach to find primary vesicoureteral reflux (VUR) and renal scar is shifted to the targeted restrictive approach. A voiding cystourethrography is not routinely recommended and is indicated only in atypical or complex clinical conditions, abnormal ultrasonography and recurrent UTIs. $^{99m}Tc$-DMSA renal scan is valuable in diagnosing pyelonephritis in children with negative culture or normal RBUS. Although it is not routinely recommended, normal scan can safely avoid VCUG. In prevention, a more natural approach is preferred. Antimicrobial prophylaxis is not supported any more even in children with VUR. Topical steroid (2-4 weeks) to non-retractile physiologic phimosis or labial adhesion is a reasonable first-line treatment. Urogenital hygiene is important and must be adequately performed. Breast milk, probiotics and cranberries are dietary factors to prevent UTIs. Voiding dysfunction and constipation should be properly treated and prevented by initiating toilet training at an appropriate age (18-24 months). The follow-up urine test on subsequent unexplained febrile illness is strongly recommended. Changes of this revision is not exclusive and appropriate variation still may be accepted.