• Genomics & Informatics
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• v.15 no.1
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• pp.48-50
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• 2017

Tumor tissues from biopsies or surgery are major sources for the next generation sequencing (NGS) study, but these procedures are invasive and have limitation to overcome intratumor heterogeneity. Recent studies have shown that driver alterations in tumor tissues can be detected by liquid biopsy which is a less invasive technique capable of both capturing the tumor heterogeneity and overcoming the difficulty in tissue sampling. However, it is still unclear whether the driver alterations in liquid biopsy can be detected by targeted NGS and how those related to the tissue biopsy. In this study, we performed whole-exome sequencing for a breast cancer tissue and identified PTEN p.H259fs*7 frameshift mutation. In the plasma DNA (liquid biopsy) analysis by targeted NGS, the same variant initially identified in the tumor tissue was also detected with low variant allele frequency. This mutation was subsequently validated by digital polymerase chain reaction in liquid biopsy. Our result confirm that driver alterations identified in the tumor tissue were detected in liquid biopsy by targeted NGS as well, and suggest that a higher depth of sequencing coverage is needed for detection of genomic alterations in a liquid biopsy.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.20 no.1
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• pp.29-35
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• 2020

Joubert syndrome (JS) is a rare genetic disorder that is characterized by ataxia, hypotonia, developmental delay, respiratory abnormalities such as apnea-hyperpnea, and abnormal eye movements. The pathognomonic diagnostic finding is the "molar tooth sign" (MTS) on brain magnetic resonance imaging (MRI), described as cerebellar vermis hypoplasia or dysplasia, thick and horizontally oriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. JS is characterized by genetic heterogeneity: pathogenic variants in over 30 genes have been identified to date. The CEP290 protein, which is on chromosome 12q21.3, is most frequently mutated in patients with JS, especially with renal involvement. Here, we report a case of JS in a 14-year-old male patient with end-stage renal disease. To the best of our knowledge, this is the first Korean report of a patient with JS due to CEP290 mutation (c.6012-12T> A) whose diagnosis was confirmed after repetitive MRI. We suggest consultation with an experienced neuro-radiologist and follow-up MRI studies to detect a "hidden" MTS if clinical findings suggest a diagnosis of JS. Furthermore, even in the absence of an MTS, whole exome sequencing should be considered.

• Journal of Genetic Medicine
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• v.17 no.1
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• pp.43-46
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• 2020

The Shprintzen-Goldberg syndrome (SGS) is an extremely rare genetic disorder caused by heterozygous variant in SKI. SGS is characterized by neurodevelopmental impairment with skeletal anomaly. Recognition of SGS is sometimes quite challenging in practice because it has diverse clinical features involving skeletal, neurological, and cardiovascular system. Here we report a case of a 6-month-old boy who initially presented with developmental delay and marfanoid facial features including prominent forehead, hypertelorism, high arched palate and retrognathia. He showed motor developmental delay since birth and could not control his head at the time of first evaluation. His height was above 2 standard deviation score. Arachnodactyly, hypermobility of joints, skin laxity, and pectus excavatum were also noted. Sequencing for FBN1 was negative, however, a novel missense variant, c.350G>A in SKI was identified by sequential whole exome sequencing. To our knowledge, this is the first case with SGS with phenotypic features of SGS overlapping with those of the Marfan syndrome, diagnosed by next generation sequencing in Korea.

• Journal of Genetic Medicine
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• v.16 no.2
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• pp.71-75
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• 2019

Periventricular nodular heterotopia (PNH) is a malformation of cortical development in which normal neurons inappropriately cluster in periventricular areas. Patients with Mowat-Wilson syndrome (MWS) typically present with facial gestalt, complex neurologic problems (e.g., severe developmental delay with marked speech impairment and epilepsy), and multiple anomalies (e.g., Hirschsprung disease, urogenital anomalies, congenital heart defects, eye anomalies, and agenesis of the corpus callosum [CC]). MWS is mostly caused by haploinsufficiency of the gene encoding zinc-finger E-box-binding homeobox 2 (ZEB2) due to premature stops or large deletions. We present a case report of a 9-year-old girl with PNH, drug-responsive epilepsy, severe intellectual disability, and facial dysmorphisms only in whom we performed whole-exome sequencing and found a de novo heterozygous missense mutation (c.3134A>C; p.His1045Pro) of ZEB2 (NM_014795.3; NP_055610.1). This mild case of MWS caused by a rare novel missense mutation of ZEB2 represents the first report of MWS with isolated PNH.

• Childhood Kidney Diseases
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• v.24 no.2
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• pp.115-119
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• 2020

Distal renal tubular acidosis (dRTA) is a rare renal tubular disorder characterized by normal anion gap metabolic acidosis, hypokalemia, and high urine pH. It can be inherited or acquired. In untreated pediatric patients with dRTA, rickets and growth retardation are common. We report the case of a 12-year-old Lao girl who presented with typical clinical features of dRTA with severe bone deformities that developed after a bed-ridden state due to a bicycle accident at the age of 8 years. Initial laboratory tests revealed metabolic acidosis with a normal anion gap, hypokalemia, and alkali urine. Renal ultrasonography revealed bilateral medullary nephrocalcinosis. Whole exome sequencing revealed no pathogenic mutations. After treatment with oral alkali, potassium, and vitamin D, she could walk and run. Later, she underwent corrective orthopedic surgeries for bony deformities. Thus, in pediatric dRTA patients, despite severe symptoms remaining untreated, accurate diagnosis and proper management can improve quality of life.

• BMB Reports
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• v.52 no.5
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• pp.304-311
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• 2019

The cytoplasmic FMR1-interacting protein family (CYFIP1 and CYFIP2) are evolutionarily conserved proteins originally identified as binding partners of the fragile X mental retardation protein (FMRP), a messenger RNA (mRNA)-binding protein whose loss causes the fragile X syndrome. Moreover, CYFIP is a key component of the heteropentameric WAVE regulatory complex (WRC), a critical regulator of neuronal actin dynamics. Therefore, CYFIP may play key roles in regulating both mRNA translation and actin polymerization, which are critically involved in proper neuronal development and function. Nevertheless, compared to CYFIP1, neuronal function and dysfunction of CYFIP2 remain largely unknown, possibly due to the relatively less well established association between CYFIP2 and brain disorders. Despite high amino acid sequence homology between CYFIP1 and CYFIP2, several in vitro and animal model studies have suggested that CYFIP2 has some unique neuronal functions distinct from those of CYFIP1. Furthermore, recent whole-exome sequencing studies identified de novo hot spot variants of CYFIP2 in patients with early infantile epileptic encephalopathy (EIEE), clearly implicating CYFIP2 dysfunction in neurological disorders. In this review, we highlight these recent investigations into the neuronal function and dysfunction of CYFIP2, and also discuss several key questions remaining about this intriguing neuronal protein.

• Journal of Genetic Medicine
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• v.17 no.2
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• pp.92-96
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• 2020

Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS) is an autosomal-dominant, extremely rare neurodevelopmental disorder caused by the heterozygous EBF3 gene mutation. EBF3 is located on chromosome 10q26.3 and acts as a transcription factor that regulates neurogenesis and differentiation. This syndrome is characterized by dysmorphism, cerebellar hypoplasia, urogenital anomaly, hypotonia, ataxia, intellectual deficit, and speech delay. The current report describes a 3-year-old Korean male carrying a de novo EBF3 mutation, c.589A>G (p.Asn197Asp), which was identified by whole exome sequencing. He manifested facial dysmorphism, hypotonia, strabismus, vermis hypoplasia, and urogenital anomalies, including vesicoureteral reflux, cryptorchidism, and areflexic bladder. This is the first report of a case of HADDS cause by an EBF3 mutation in the Korean population.

• Journal of Genetic Medicine
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• v.18 no.2
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• pp.137-141
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• 2021

Genetic causes of developmental and epileptic encephalopathy (DEE) have been rapidly uncovered from mid-2010s. The mutations of gene enconding calcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) are recently detected in DEE, which gene is already known well in familial hemiplegic migrine type 1 or episodic ataxia type 2. Ketogenic diet therapy (KDT) is effective in some DEE, which data is short in CACNA1A encephalopathy. A 3-month-old male with global developmental delay and multidrug-resistant focal seizures was diagnosed as epilepsy of infancy with migrating focal seizures (EIMFS). Brain magnetic resonance imaging and metabolic screening were all normal. Whole exome sequencing revealed two variants of CACNA1A: c.899A>C, and c.2808del that is from his mother. His seizures disappeared within 3 days whenever on KDT, which recurred without it. To our knowledge, this rare case of EIMFS with novel mutations of CACNA1A, is the first report in CACNA1A encephalopathy becoming seizure-free on KDT.

• Childhood Kidney Diseases
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• v.26 no.1
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• pp.63-67
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• 2022

Nephrocalcinosis often occurs in infants and is caused by excessive calcium or vitamin D supplementation, neonatal primary hyperparathyroidism, and genetic disorders. Idiopathic infantile hypercalcemia (IIH), a rare cause of nephrocalcinosis, results from genetic defects in CYP24A1 or SLC34A1. Mutations in CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, disrupt active vitamin D degradation. IIH clinically manifests as failure to thrive and hypercalcemia within the first year of life and usually remits spontaneously. Herein, we present a case of IIH wih CYP24A1 mutations. An 11-month-old girl visited our hospital with incidental hypercalcemia. She showed failure to thrive, and her oral intake had decreased over time since the age of 6 months. Her initial serum parathyroid hormone level was low, 25-OH vitamin D and 1,25(OH)₂ vitamin D levels were normal, and renal ultrasonography showed bilateral nephrocalcinosis. Whole-exome sequencing revealed compound heterozygous variants in CYP24A1 (NM_000782.4:c.376C>T [p.Pro126Ser] and c.1310C>A [p.Pro437His]). Although her hypercalcemia and poor oral intake spontaneously resolved in approximately 8 months, we suggested that her nephrocalcinosis and renal function be regularly checked in consideration of potential asymptomatic renal damage. Hypercalcemia caused by IIH should be suspected in infants with severe nephrocalcinosis, especially when presenting with failure to thrive.

• Journal of Genetic Medicine
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• v.19 no.2
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• pp.115-119
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• 2022

The 46,XX testicular disorder of sex development (DSD) is a rare condition in which 46,XX individuals develop testicular differentiation and virilization. Translocation of the sex-determining region Y (SRY) onto the X chromosome is the main cause of 46,XX testicular DSD, whereas dysregulation between pro-testis and pro-ovarian genes can induce SRY-negative 46,XX testicular DSD. Nuclear receptor subfamily 5 group A member 1 (NR5A1), a nuclear receptor transcription factor, plays an essential role in gonadal development in XY and XX embryos. Herein, we report the first Korean case of SRY-negative 46,XX testicular DSD with a heterozygous NR5A1 p.Arg92Trp variant. The patient presented with a small penis, bifid scrotum, and bilateral undescended testes. Whole exome sequencing revealed a heterozygous missense variant (c.274C>T) of NR5A1. Our case highlights that NR5A1 gene variants need to be considered important causative factors of SRY-negative non-syndromic 46,XX testicular DSD.