• 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.

• Genes and Genomics
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• v.40 no.12
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• pp.1269-1277
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• 2018

Bcl2-associated athanogene 3 (BAG3) mutations have been reported to cause the myofibrillar myopathy (MFM) which shows progressive limb muscle weakness, respiratory failure, and cardiomyopathy. Myopathy patients with BAG3 mutation are very rare. We described a patient showing atypical phenotypes. We aimed to find the genetic cause of Korean patients with sensory motor polyneuropathy, myopathy and rigid spine. We performed whole exome sequencing (WES) with 423 patients with sensory motor polyneuropathy. We found BAG3 mutation in one patient with neuropathy, myopathy and rigid spine syndrome, and performed electrophysiological study, whole body MRI and muscle biopsy on the patient. A de novo heterozygous p.Pro209Leu (c.626C>T) mutation in BAG3 was identified in a female myopathy. She first noticed a gait disturbance and spinal rigidity at the age of 11, and serum creatine kinase levels were elevated ninefolds than normal. She showed an axonal sensory-motor polyneuropathy like Charcot-Marie-Tooth disease (CMT), myopathy, rigid spine and respiratory dysfunction; however, she did not show any cardiomyopathy, which is a common symptom in BAG3 mutation. Lower limb MRI and whole spine MRI showed bilateral symmetric fatty atrophy of muscles at the lower limb and paraspinal muscles. When we track traceable MRI 1 year later, the muscle damage progressed slowly. As far as our knowledge, this is the first Korean patient with BAG3 mutation. We described a BAG3 mutation patient with atypical phenotype of CMT and myopathy, and those are expected to broaden the clinical spectrum of the disease and help to diagnose it.

• Journal of Platform Technology
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• v.6 no.4
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• pp.87-95
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• 2018

With the decrease of sequencing price, many national projects that analyzes 0.1 to 1 million people are now in progress. However, large portion of budget of these large projects is dedicated for construction of the cluster system or purchase servers, due to the lack of programs or systems that can handle large amounts of data simultaneously. In this study, we developed NGSOne, a client program that is easy-to-use for even biologists, and performs SNP analysis using hundreds or more of Whole Genome and Whole Exome analysis without construction of their own server or cluster environment. DRAGEN, BWA / GATK, and Isaac / Strelka2, which are representative SNP analysis tools, were selected and DRAGEN showed the best performance in terms of execution time and number of errors. Also, NGSOne can be extended for various analysis tools as well as SNP analysis tools.

• Journal of Genetic Medicine
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• v.16 no.1
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• pp.39-42
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• 2019

KBG syndrome is an autosomal dominant syndrome presenting with macrodontia, distinctive facial features, skeletal anomalies, and neurological problems caused by mutations in the ankyrin repeat domain 11 (ANKRD11) gene. The diagnosis of KBG is difficult in very young infants as the characteristic macrodontia and typical facial features are not obvious. The youngest patient diagnosed to date was almost one year of age. We here describe a 2-month-old Korean boy with distinctive craniofacial features but without any evidence of macrodontia due to his very early age. He also had a congenital megacolon without ganglion cells in the rectum. A de novo deletion of exons 5-9 of the ANKRD11 gene was identified in this patient by exome sequencing and real-time genomic polymerase chain reaction. As ANKRD11 is involved in the development of myenteric plexus, a bowel movement disorder including a congenital megacolon is not surprising in a patient with KBG syndrome and has possibly been overlooked in past cases.

• Journal of Genetic Medicine
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• v.18 no.2
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• pp.142-146
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• 2021

Alagille syndrome (AGS) is a rare autosomal dominant inherited disorder, with major clinical manifestations of bile duct paucity, cholestasis, cardiovascular anomaly, ophthalmic abnormalities, butterfly vertebrae, and dysmorphic facial appearance. It is caused by heterozygous mutations in JAG1 or NOTCH of the Notch signaling pathway presenting with variable phenotypic penetrance and involving multiple organ systems. The following case report describes a unique case of a 16-year-old female with AGS who presented with the primary complaint of renovascular hypertension. She had a medical history of ventricular septal defect and polycystic ovary syndrome. The patient had a dysmorphic facial appearance including frontal bossing, bulbous tip of the nose, a pointed chin with prognathism, and deeply set eyes with mild hypertelorism. Stenoocclusive changes of both renal arteries, celiac artery, lower part of the abdominal aorta, and left intracranial artery, along with absence of the left internal carotid artery were found on examination. Whole exome sequencing was performed and revealed a pathologic mutation of JAG1, leading to the diagnosis of AGS. Reverse phenotyping detected butterfly vertebrae and normal structure and function of the liver and gallbladder. While the representative symptom of AGS in most scenarios is a hepatic problem, in this case, the presenting clinical features were the vascular anomalies. Clinical manifestations of AGS are diverse, and this case demonstrates that renovascular hypertension might be in some cases a presenting symptom of AGS.

• 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.

• The Journal of the Korea Contents Association
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• v.22 no.2
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• pp.762-769
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• 2022

Genetic testing in prenatal diagnosis is a precious tool providing valuable information in clinical management and parental decision-making. For the last year, cytogenetic testing methods, such as G-banding karyotype analysis, fluorescent in situ hybridization, chromosomal microarray, and gene panels have evolved to become part of routine laboratory testing. However, the limitations of each of these methods demonstrate the need for a revolutionary technology that can alleviate the need for multiple technologies. The recent introduction of new genomic technologies based on next-generation sequencing has changed the current practice of prenatal testing. The promise of these innovations lies in the fast and cost-effective generation of genome-scale sequence data with exquisite resolution and accuracy for prenatal diagnosis. Here, we review the current state of sequencing-based pediatric diagnostics, associated challenges, as well as future prospects.

• Journal of Genetic Medicine
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• v.19 no.1
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• pp.32-37
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• 2022

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase B due to mutations in the ARSB gene. Here, we report the case of a Korean female with a novel variant of MPS VI. A Korean female aged 5 years and 8 months, who is the only child of a healthy non-consanguineous Korean couple, presented at our hospital for severe short stature. She had a medical history of umbilical hernia and recurrent otitis media. Her symptoms included snoring and mouth breathing. Subtle dysmorphic features, including mild coarse face, joint contracture, hepatomegaly, and limited range of joint motion, were identified. Radiography revealed deformities, suggesting skeletal dysplasia. Growth hormone (GH) provocation tests revealed complete GH deficiency. Targeted exome sequencing revealed compound heterozygous mutations in the ARSB genes c.512G>A (p.Gly171Asp; a pathogenic variant inherited from her father) and c.1157C>T (p.Ser386Phe; a novel variant inherited from her mother in familial genetic testing). Quantitative tests revealed increased urine glycosaminoglycan (GAG) levels and decreased enzyme activity of arylsulfatase B. While on enzyme replacement therapy and GH therapy, her height increased drastically; her coarse face, joint contracture, snoring, and obstructive sleep apnea improved; urine GAG decreased; and left ventricular mass index was remarkably decreased. We report a novel variant-c.1157C>T (p.Ser386Phe)-of the ARSB gene in a patient with MPS VI; these findings will expand our knowledge of its clinical spectrum and molecular mechanisms.

• Journal of Genetic Medicine
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• v.19 no.2
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• pp.85-93
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• 2022

Purpose: Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder caused by genetic variants of the cohesin complex. However, the diverse genetic etiologies and their phenotypic correlations in Korean patients with CdLS are still largely unknown. Hence, this study aimed to clarify the clinical characteristics and genetic background of Korean patients with CdLS. Materials and Methods: The medical records of 15 unrelated patients (3 males and 12 females) genetically confirmed to have CdLS were retrospectively reviewed. All individuals were diagnosed with CdLS using target gene analysis, whole-exome sequencing, and/or chromosomal microarray analysis. The clinical score (CS) was calculated to assess disease severity. Results: The median age at diagnosis was 1.7 (range, 0.0-11.8) years, and median follow-up duration was 3.8 (range, 0.4-11.7) years. Eight (53.3%) patients showed classic phenotypes of CdLS, two (13.3%) showed non-classic phenotypes, and five (33.3%) had other phenotypes sharing limited signs of CdLS. Fifteen causative variants were identified: NIPBL in five (33.3%, including 3 males), SMC1A in three (20.0%), SMC3 in three (20.0%), and HDAC8 in four (26.7%) patients. The CS was significantly higher in the NIPBL group than in the non-NIPBL group (14.2±1.3 vs. 8.7±2.9, P<0.001). Conclusion: We identified the clinical and genetic heterogeneity of CdLS in Korean patients. Patients with variants of NIPBL had a more distinctive phenotype than those carrying variants of other cohesin complex genes (SMC1A, SMC3, and HDAC8). However, further studies are warranted to understand the pathogenesis of CdLS as a cohesinopathy and its genotype-phenotype correlations.

• Journal of Genetic Medicine
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• v.19 no.2
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• pp.94-99
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• 2022

Lesch-Nyhan disease (LND) is a rare X-linked recessive inherited purine metabolic disorder that accompanies neurodevelopmental problems. Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant inherited genetic disorder characterized by tumors in various systems. Some children with NF1 also accompanies neurodevelopmental problems. Here, we describe a 5-year-old boy with a maternally inherited pathogenic variant in NF1 and hypoxanthine-guanine phosphoribosyltransferase (HPRT). He was referred for severe neurodevelopmental impairment and hyperuricemia. His mother was diagnosed with NF1 and the patient was also suspected of having NF1 because of cafe au lait macules. He had dystonia, rigidity, cognitive deficit, and speech/language impairment. Serum and urine uric acid concentrations were elevated. He had more severe neurodevelopmental delay than patients with only NF1, so his clinical symptoms could not be fully understood by the disease alone. To find the cause of his neurologic symptoms and hyperuricemia, the patient and his mother underwent a whole-exome sequencing test. As a result, the pathogenic variant c.151C>T (p.Arg51Ter) in HPRT1 was identified as hemizygote in the patient and heterozygote in his mother. The pathogenic variant c.7682C>G (p.Ser2561Ter) in NF-1 was identified as heterozygotes in both of them. Although the clinical symptoms of both diseases were overlapping and complicated, genetic testing was helpful for accurate diagnosis and treatment. Therefore, we suggest to consider preemptive genetic evaluation if there are symptoms not sufficiently explained by known existing diseases. And it is considered valuable to review this rare case to understand the clinical course and possible synergic effects of these diseases.