• Clinical and Experimental Pediatrics
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• v.53 no.10
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• pp.909-912
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• 2010

Familial hypokalemic periodic paralysis is an autosomal-dominant channelopathy characterized by episodic muscle weakness with hypokalemia. The respiratory and cardiac muscles typically remain unaffected, but we report an atypical case of a family with hypokalemic periodic paralysis in which the affected members presented with frequent respiratory insufficiency during severe attacks. Molecular analysis revealed a heterozygous c.664 C>T transition in the sodium channel gene $SCN4A$, leading to an Arg222Trp mutation in the channel protein. The patients described here presented unusual clinical characteristics that included a severe respiratory phenotype, an incomplete penetrance in female carriers, and a different response to medications.

• Clinical and Experimental Pediatrics
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• v.59 no.sup1
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• pp.1-4
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• 2016

Congenital aniridia is a rare ocular malformation that presents with severe hypoplasia of the iris and various ocular manifestations. Most cases of congenital aniridia are known to be related to mutations in the paired box gene-6 (PAX6 ), which is an essential gene in eye development. Herein, we report a familial case of autosomal dominant congenital aniridia with four affected members in 3 consecutive generations and describe the detailed ophthalmologic findings for one of these members. As expected, mutational analysis revealed a nonsense mutation (p.Ser122*) in the PAX6 gene. Thus, our findings reiterate the importance of PAX6 mutations in congenital aniridia.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.2027-2033
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• 2014

Background: We aimed to assess RET proto-oncogene polymorphisms in three different Iranian families with medullary thyroid cancer (MTC), and performed molecular dynamics simulations and free energy stability analysis of these mutations. Materials and Methods: This study consisted of 48 patients and their first-degree relatives with MTC confirmed by pathologic diagnosis and surgery. We performed molecular dynamics simulations and free energy stability analysis of mutations, and docking evaluation of known RET proto-oncogene inhibitors, including ZD-6474 and ponatinib, with wild-type and mutant forms. Results: The first family consisted of 27 people from four generations, in which nine had the C.G2901A (P.C634Y) mutation; the second family consisted of six people, of whom three had the C.G2901T (P.C634F) mutation, and the third family, who included 12 individuals from three generations, three having the C.G2251A (P.G691S) mutation. The automated 3D structure of RET protein was predicted using I-TASSER, and validated by various protein model verification programs that showed more than 96.3% of the residues in favored and allowed regions. The predicted instability indices of the mutated structures were greater than 40, which reveals that mutated RET protein is less thermo-stable compared to the wild-type form (35.4). Conclusions: Simultaneous study of the cancer mutations using both in silico and medical genetic procedures, as well as onco-protein inhibitor binding considering mutation-induced drug resistance, may help in better overcoming chemotherapy resistance and designing innovative drugs.

• Clinical and Experimental Pediatrics
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• v.56 no.6
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• pp.265-268
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• 2013

Wiskott-Aldrich syndrome (WAS) is an inherited X-linked disorder. The WAS gene is located on the X chromosome and undergoes mutations, which affect various domains of the WAS protein, resulting in recurrent infection, eczema, and thrombocytopenia. However, the clinical features and severity of the disease vary according to the type of mutations in the WAS gene. Here, we describe the case of a 4-year-old boy with a history of marked thrombocytopenia since birth, who presented with recurrent herpes simplex infection and late onset of eczema. Examination of his family history revealed that older brother, who died from intracranial hemorrhage, had chronic idiopathic thrombocytopenia. Therefore, we proceeded with genetic analysis and found a new deletion mutation in the WAS gene: c.858delC (p.ser287Leufs$^*21$) as a hemizygous form.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.20 no.2
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• pp.114-123
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• 2017

Purpose: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. Methods: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. Results: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. Conclusion: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.

• Journal of Genetic Medicine
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• v.14 no.2
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• pp.56-61
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• 2017

Purpose: Neurofibromatosis type 2 (NF2) is characterized by multiple tumors, including vestibular schwannoma (VS) and others affecting cranial and peripheral nerves. NF2 is caused by mutation of the NF2 gene. The mutation spectrum of NF2 has not been characterized in Korean patients. In the current study, the clinical and genetic characteristics of Korean NF2 patients were analyzed. Materials and Methods: Twenty-five unrelated Korean families were enrolled according to the Manchester criteria. Genetic analysis was performed by direct sequencing and multiplex ligation-dependent probe amplification methods using genomic DNA from peripheral lymphocytes or tumor tissues. Results: All patients had bilateral/unilateral VS and/or other cranial and peripheral nerve tumors. Two patients were familial cases and the other 24 patients were sporadic. Germline NF2 mutations were detected in peripheral lymphocytes from both familial cases, but only in 26.1% of the 23 sporadic families. Somatic mutations were also found in tumor tissues from two of the sporadic families. These somatic mutations were not found in peripheral lymphocytes. A total of 10 different mutations including 2 novel mutations were found in 40.0% of studied families. Five mutations (50.0%) were located in exon 6 of NF2, the FERM domain coding region. Conclusion: Family history was an important factor in identifying germline NF2 mutations. Further study is required to investigate whether exon 6 is a mutation hotspot in Korean NF2 patients and its correlation to phenotypic severity.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.1977-1980
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• 2015

Objective: The Von Hippel-Lindau syndrome (VHLD), an inherited neoplastic syndrome predisposing to central nervous system hemangioblastoma (CNS), pheochromocytoma (PCC), renal cell carcinoma(RCC), retinal hemangioma (RA) and renal cysts, is caused by mutations or deletions of the VHL tumor-suppressor gene. To assess VHL genotype-phenotype correlations with function of pVHL a gene mutation analysis of members in a Chinese family with non-syndromic PCCs and individuals with apparently sporadic pheochromocytoma (ASP) was performed. Materials and Methods: DNA samples of 20 members from the Chinese family with non-syndromic PCCs and 41 patients with ASP were analyzed by polymerase chain reaction and direct sequencing, confirmed by Taqman probe. Results: Three novel mutations (H125P, 623(^TTTGTtG) and R120T) were identified in the Chinese family and in 3 among 41 ASP patients. The mutations were all located in exon 2 of VHL gene encoding ${\beta}$-domain of pVHL. The tumor type in H125P carriers and R120T carriers was VHL type 2C. And 623(^TTTGTtG) carriers presented VHL type 2B or type 2C. Conclusions: VHL gene abnormalities were identified in the Chinese family with non-syndromic PCCs and patients with APS, resulting in dysfunction of pVHL. H125P and R120T could be associated with VHL type 2C, while 623(^TTTGTtG) might be linked with VHL type 2B or type 2C. Not only is the genetic analysis helpful for early diagnosis and treatment of patients with VHLD, it is also benefitial for research intoVHLD pathogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1539-1546
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• 2016

Specific patterns of the hereditary breast and ovarian cancer (HBOC) syndrome are related to mutations in the BRCA1 gene. One hundred unrelated breast cancer patients were interviewed to obtain clinical symptoms and signs, pedigree and familial history of HBOC syndrome related cancer. Subsequently, data were calculated using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk prediction model. Patients with high score of BOADICEA were offered genetic testing. Eleven patients with high score of BOADICEA, 2 patients with low score of BOADICEA, 2 patient's family members and 15 controls underwent BRCA1 genetic testing. Mutation screening using PCR-HRM was carried out in 22 exons (41 amplicons) of BRCA1 gene. Sanger sequencing was subjected in all samples with aberrant graph. This study identified 10 variants in the BRCA1 gene, consisting of 6 missense mutations (c.1480C>A, c.2612C>T, c.2566T>C, c.3113A>G, c.3548 A>G, c.4837 A>G), 3 synonymous mutations (c.2082 C>T, c.2311 T>C and c.4308T>C) and one intronic mutation (c.134+35 G>T). All variants tend to be polymorphisms and unclassified variants. However, no known pathogenic mutations were found.

• Journal of Genetic Medicine
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• v.16 no.2
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• pp.67-70
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• 2019

Limb-girdle muscular dystrophy (LGMD) is a group of muscular dystrophies that has extremely heterogeneous clinical features and genetic background. The caveolin-3 gene (CAV3) is one of the causative genes. LGMD appears as a clinical continuum, from isolated skeletal muscle involvement to long QT syndrome. Here we report two patients without apparent muscle weakness in a family with CAV3 mutation. A 7-month-old Korean boy visited our muscle clinic because of an incidental finding of elevated serum creatine kinase (CK) concentration (680 IU/L, reference range, 20-270 IU/L) without clinical symptoms. The patient was born after an uneventful pregnancy and showed normal developmental milestones. He developed pseudohypertrophy of his calf muscle during the follow-up. We obtained a muscle biopsy at age 14 months, which showed size variations and degenerating/regenerating myofibers with endomysial fibrosis and immunohistochemical evidence of normal dystrophin. Under the impression of LGMD, we performed target panel sequencing and identified a heterozygous in-frame mutation of CAV3, c.307_312delGTGGTG (p.Val103_Val104del). Immunohistochemical staining of muscle indicated complete loss of caveolin-3 compared with normal control muscle, which supported the variant's pathogenicity. We performed segregation analysis and found that the patient's mother had the same variant with elevated serum CK level (972 IU/L). We report on autosomal dominant familial caveolinopathy caused by a pathogenic variant in CAV3, which was asymptomatic until the fourth decade. This case highlights the utility of next generation sequencing in the diagnosis of muscular dystrophies and the additive role of muscle biopsy to confirm the variants.

• Archives of Plastic Surgery
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• v.39 no.3
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• pp.184-189
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• 2012

Keloid disease is a fibroproliferative dermal tumor with an unknown etiology that occurs after a skin injury in genetically susceptible individuals. Increased familial aggregation, a higher prevalence in certain races, parallelism in identical twins, and alteration in gene expression all favor a remarkable genetic contribution to keloid pathology. It seems that the environment triggers the disease in genetically susceptible individuals. Several genes have been implicated in the etiology of keloid disease, but no single gene mutation has thus far been found to be responsible. Therefore, a combination of methods such as association, gene-gene interaction, epigenetics, linkage, gene expression, and protein analysis should be applied to determine keloid etiology.