• Genomics & Informatics
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• v.11 no.4
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• pp.239-244
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• 2013

Somatic mutation is a major cause of cancer progression and varied responses of tumors against anticancer agents. Thus, we must obtain and characterize genome-wide mutational profiles in individual cancer subtypes. The Cancer Genome Atlas database includes large amounts of sequencing and omics data generated from diverse human cancer tissues. In the present study, we integrated and analyzed the exome sequencing data from ~3,000 tissue samples and summarized the major mutant genes in each of the diverse cancer subtypes and stages. Mutations were observed in most human genes (~23,000 genes) with low frequency from an analysis of 11 major cancer subtypes. The majority of tissue samples harbored 20-80 different mutant genes, on average. Lung cancer samples showed a greater number of mutations in diverse genes than other cancer subtypes. Only a few genes were mutated with over 5% frequency in tissue samples. Interestingly, mutation frequency was generally similar between non-metastatic and metastastic samples in most cancer subtypes. Among the 12 major mutations, the TP53, USH2A, TTN, and MUC16 genes were found to be frequent in most cancer types, while BRAF, FRG1B, PBRM1, and VHL showed lineage-specific mutation patterns. The present study provides a useful resource to understand the broad spectrum of mutation frequencies in various cancer types.

• Journal of Genetic Medicine
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• v.18 no.2
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• pp.127-131
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• 2021

Autosomal recessive spinocerebellar ataxia 20 (SCAR20; OMIM #616354) is a recently described disorder that is characterized by ataxia, intellectual disability, cerebellar atrophy, macrocephaly, coarse face, and absent speech. It is caused by loss-of-function mutations in SNX14. To date, all cases with homozygous pathogenic variants have been identified in consanguineous families. This report describes the first Korean cases of SCAR20 family caused by homozygous variants in SNX14. Two siblings were referred to our clinic because of severe global developmental delay. They presented similar facial features, including a high forehead, long philtrum, thick lips, telecanthus, depressed nasal bridge, and broad base of the nose. Because the older sibling was unable to walk and newly developed ataxia, repeated brain magnetic resonance imaging (MRI) was performed at the age of 4 years, revealing progressive cerebellar atrophy compared with MRI performed at the age of 2 years. The younger sibling's MRI revealed a normal cerebellum at the age of 2 years. Whole-exome sequencing was performed, and homozygous variants, such as c.2746-2A>G, were identified in SNX14 from the older sibling. Sanger sequencing confirmed homozygous SNX14 variants in the two siblings as well as a heterozygous variant in both parents. This report extends our knowledge of the phenotypic and mutational spectrum of SCAR20. We also highlight the importance of deep phenotyping for the diagnosis of SCAR20 in individuals with developmental delay, ataxia, cerebellar atrophy, and distinct facial features.

• Journal of Genetic Medicine
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• v.21 no.1
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• pp.31-35
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• 2024

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked neurodevelopmental disorder with abnormal thyroid function caused by mutation in the solute carrier family 16 member 2 (SLC16A2) gene. Clinical manifestations of AHDS are global or axial hypotonia, a variety of movement disorders, severe intellectual disability, quadriplegia or spastic diplegia, growth failure, and seizures. A 10-year-old boy visited our hospital with the chief complaint of newly onset generalized tonic seizures with vocalization of weekly to daily frequency. He showed early infantile hypotonia, severe intellectual disability, and frequent respiratory infections. He could not walk independently and was non-verbal. Electroencephalogram revealed generalized slow spike and waves with multifocal spikes and slow background rhythms. His tonic seizures were controlled with more than two anti-seizure medications (ASMs). At 11 years of age, he was evaluated for thyroid function as part of regular screening for ASM maintenance and was found to have abnormal thyroid function. We performed whole exome sequencing for severe global developmental delay, drug-resistant epilepsy, and abnormal thyroid function. The hemizygous c.940C>T (p.Arg314Ter) variant in the SLC16A2 gene (NM_006517.5) was identified and confirmed based on Sanger sequencing. Herein, we describe a case of an AHDS patient with late-onset drug-resistant epilepsy combined with congenital hypotonia, global developmental delay, and abnormal thyroid function results. To the best of our knowledge, this is the oldest adolescent among AHDS cases reported in Korea. In this report, clinical characteristics of a mid-adolescence patient with AHDS were presented.

• 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.

• Neonatal Medicine
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• v.25 no.3
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• pp.126-130
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• 2018

Parkes Weber syndrome is a rare congenital vascular anomaly, related to the RAS p21 protein activator 1 (RASA1) gene. It is characterized by capillary cutaneous malformations, bony and soft tissue hyperplasia, and multiple arteriovenous fistulas throughout the affected upper or lower extremity. These arteriovenous fistulas can be associated with life-threatening complications such as bleeding, thrombosis, and high output heart failure. In this report, we present a neonate who had a disproportionately hypertrophied left upper limb with port-wine stain, dystrophy of the left humerus, and hypertrophy of the left clavicle on X-ray, and arteriovenous malformation and massive dilatation of the left subclavian artery on magnetic resonance angiography. Exome sequencing analysis revealed a novel heterozygous splicing mutation (c.1776+2T>A) in the RASA1 gene. To the best of our knowledge, this report is the first case of RASA1-related Parkes Weber syndrome in Korea.

• 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.