Congenital myotonic dystrophy (CMD) which is transmitted in an autosomal-dominant manner, can also be observed in newborns born to asymptomatic parents who have a myotonic dystrophy type 1 or premutation allele, especially from the mother. A mother with myotonic dystrophy could be subfertile and the pregnancy could be complicated with the risk of a preterm birth. Newborns with CMD may demonstrate symptoms such as hypotonia and poor motor activity, as well as respiratory and feeding difficulties. Additionally, CMD has a high mortality rate at birth. Detection of the signs and symptoms during pregnancy is helpful for a prenatal diagnosis of CMD in cases where the family history is not known.
Alleles ; Genetic Counseling ; Humans ; Infant, Newborn ; Mortality ; Mothers ; Motor Activity ; Muscle Hypotonia ; Myotonic Dystrophy* ; Parents ; Parturition ; Postpartum Period ; Pregnancy ; Premature Birth ; Prenatal Diagnosis

Cantú syndrome (CS, OMIM 239850) is a very rare autosomal dominantly inherited genetic disease characterized by congenital hypertrichosis, neonatal macrosomia, a distinct facial features such as macrocephaly, and cardiac defects. Since the first description by Cantú et al. in 1982, about 50 cases have been reported to date. Recently, two causative genes for CS has been found by using exome sequencing analyses: ABCC9 and KCNJ8 . Most cases of clinically diagnosed CS have resulted from de novo mutations in ABCC9. In this study, we report three independent Korean children with CS resulting from de novo ABCC9 mutations. Our patients had common clinical findings such as congenital hypertrichosis, distinctive facial features. One of them showed severe pulmonary hypertension and hypertrophic cardiomyopathy, which require medical treatment. And, two patients had a history of patent ductus arteriosus. Although two of our patients had shown early motor developmental delay, it was gradually improved during follow-up periods. Although CS is quite rare, there are the concerns about development of various cardiac problems in the lifetime. Therefore, an accurate diagnosis followed by appropriate management and genetic counseling should be provided to CS patients.
Cardiomyopathy, Hypertrophic ; Child ; Databases, Genetic ; Diagnosis ; Ductus Arteriosus, Patent ; Exome ; Follow-Up Studies ; Genetic Counseling ; Humans ; Hypertension, Pulmonary ; Hypertrichosis ; Megalencephaly

CHARGE syndrome (coloboma, heart defects, atresia choanae, retarded growth and development, genital hypoplasia, and ear abnormalities) is characterized by multiple malformations and is diagnosed using distinct consensus criteria. Mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7) are the major cause of CHARGE syndrome. Clinical features of CHARGE syndrome considerably overlap those of 22q11.2 deletion syndrome. Of these features, immunodeficiency and hypocalcemia are frequently reported in patients with 22q11.2 deletion syndrome but are rarely reported in patients with CHARGE syndrome. In this report, we have described the case of a patient with typical phenotypes of 22q11.2 deletion syndrome but without the proven chromosome microdeletion. Mutation analysis of CHD7 identified a pathogenic mutation (c.2238+1G>A) in this patient. To our knowledge, this is the first case of CHARGE syndrome with immunodeficiency and hypocalcemia in Korea. Our observations suggest that mutation analysis of CHD7 should be performed for patients showing the typical phenotypes of 22q11.2 deletion syndrome but lacking the proven chromosome microdeletion.
CHARGE Syndrome* ; Consensus ; DiGeorge Syndrome ; Ear ; Growth and Development ; Heart ; Humans ; Hypocalcemia* ; Korea ; Nasopharynx ; Phenotype

We herein report an analysis of a female baby with a de novo dup(10p)/del(10q) chromosomal aberration. A prenatal cytogenetic analysis was performed owing to abnormal ultrasound findings including a choroid plexus cyst, prominent cisterna magna, and a slightly medially displaced stomach. The fetal karyotype showed additional material attached to the terminal region of chromosome 10q. Parental karyotypes were both normal. At birth, the baby showed hypotonia, upslanting palpebral fissures, a nodular back mass, respiratory distress, neonatal jaundice and a suspicious polycystic kidney. We ascertained that the karyotype of the baby was 46,XX,der(10)(pter-->q26.3::p11.2-->pter) by cytogenetic and molecular cytogenetic analyses including high resolution GTG- and RBG-banding, fluorescence in situ hybridization, comparative genomic hybridization, and short tandem repeat marker analyses. While almost all reported cases of 10p duplication originated from one of the parents with a pericentric inversion, our case is extraordinarily rare as the de novo dup(10p)/del(10q) presumably originated from a rearrangement at the premeiotic stage of the parental germ cell or from parental germline mosaicism.
Choroid Plexus ; Chromosome Aberrations ; Chromosomes, Human, Pair 10 ; Cisterna Magna ; Comparative Genomic Hybridization ; Cytogenetic Analysis ; Cytogenetics ; Female ; Fluorescence ; Germ Cells ; Humans ; In Situ Hybridization ; Infant, Newborn ; Jaundice, Neonatal ; Karyotype ; Korea ; Microsatellite Repeats ; Mosaicism ; Muscle Hypotonia ; Parents ; Parturition ; Polycystic Kidney Diseases ; Stomach ; Ultrasonography

Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by the classic triad of congenital anomalies of the anus, thumbs, and ears, with variable expressivity. Additionally, renal malformations, cardiac anomalies, and endocrine and eye abnormalities can accompany TBS, although less frequently. TBS is inherited in an autosomal dominant fashion; however, about 50% of patients have a family history of TBS and the remaining 50% have de novo mutations. SALL1, located on chromosome 16q12.1, is the only causative gene of TBS. SALL1 acts as a transcription factor and may play an important role in inducing the anomalies during embryogenesis. Clinical features of TBS overlap with those of other multiple anomaly syndromes, such as VACTERL syndrome, Baller-Gerold syndrome, Goldenhar syndrome, cat eye syndrome, and Holt-Oram syndrome. Consequently, there are some difficulties in differential diagnosis based on clinical manifestations. Herein, we report a Korean family with two generations of TBS that was diagnosed based on physical examination findings and medical history. Although the same mutation in SALL1 was identified in both the mother and the son, they displayed different clinical manifestations, suggesting a phenotypic diversity of TBS.
Anal Canal ; Animals ; Anus, Imperforate ; Cats ; Diagnosis, Differential ; Ear ; Embryonic Development ; Eye Abnormalities ; Family Characteristics ; Female ; Goldenhar Syndrome ; Hearing Loss, Sensorineural ; Humans ; Mothers ; Physical Examination ; Polydactyly ; Pregnancy ; Thumb ; Transcription Factors

PURPOSE: Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders with diverse modes of inheritance. There are several subtypes of SCAs. SCA 8, SCA 12, and SCA 17 are the less common forms of SCAs with limited information available on their epidemiological profiles in Korea. The purpose of this study was to investigate the prevalence of SCA8, SCA12, and SCA17 in Korea. MATERIALS AND METHODS: Ninety-six unrelated Korean patients were enrolled and showed normal trinucleotide repeats through polymerase-chain reaction (PCR) for the genes ATXN1, ATXN2, ATXN3, CACNA1A , and ATXN7, which correspond to SCA1, SCA2, SCA3, SCA6, and SCA7, respectively. PCR products from patients were further analyzed by capillary electrophoresis using fluorescence labeled primers for the genes ATXN8OS, PPP2R2B, and TBP, which correspond to SCA8, SCA12, and SCA17. RESULTS: Three patients had 104, 97, and 75 abnormal expanded repeats in the ATXN8OS gene, the causative gene for SCA8. None of the patients exhibited abnormal repeats in SCA12 and SCA17. Normal trinucleotide repeat ranges of the cohort in this study were estimated to be 17-34 copies (average, 24+/-4 copies) for SCA8, 7-18 copies (average, 13+/-3 copies) for SCA12, and 26-43 copies (average, 35+/-2 copies) for SCA17. CONCLUSION: This study demonstrated that SCA8, SCA12, and SCA17 are rare in Korean patients with SCA, and further genetic studies are warranted to enhance the mutation detection rate in the Korean SCA population.
Asian Continental Ancestry Group ; Cohort Studies ; Electrophoresis, Capillary ; Fluorescence ; Humans ; Korea ; Neurodegenerative Diseases ; Polymerase Chain Reaction ; Prevalence ; Repetitive Sequences, Nucleic Acid* ; Spinocerebellar Ataxias* ; Trinucleotide Repeats ; Wills

PURPOSE: We investigated the neurogenic potentials of amniotic fluid-derived stem cells (AFSCs) according to the expression levels of stem cell markers and ingredients in the neural induction media. MATERIALS AND METHODS: Four samples of AFSCs with different levels of Oct-4 and c-kit expression were differentiated neurally, using three kinds of induction media containing retinoic acid (RA) and/or a mixture of 3-isobutyl-1-methylxanthine/indomethacin/insulin (neuromix), and examined by immunofluorescence and reverse transcription-polymerase chain reaction (RT-PCR) for their expression of neurospecific markers. RESULTS: The cells in neuromix-containing media displayed small nuclei and long processes that were characteristic of neural cells. RT-PCR analysis revealed that the number of neural markers showing upregulation was greater in cells cultured in the neuromix-containing media than in those cultured in RA-only medium. Neurospecific gene expression was also higher in Oct-4 and c-kit double-positive cells than in c-kit-low or -negative cells. CONCLUSION: The stem cell marker c-kit (rather than Oct-4) and the ingredient neuromix (rather than RA) exert greater effects on neurogenesis of AFSCs.
Amniotic Fluid ; Female ; Fluorescent Antibody Technique ; Gene Expression ; Humans ; Neurogenesis ; Stem Cells* ; Tretinoin ; Up-Regulation

PURPOSE: Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy mainly divided into CMT type 1 (CMT1) and CMT2 according to the phenotype and genotype. Although molecular pathologies for each genetic causative have not been revealed in CMT2, the correlation between cell death and accumulation of misfolded proteins in the endoplasmic reticulum (ER) of Schwann cells is well documented in CMT1. Establishment of in vitro models of ER stress-mediated Schwann cell death might be useful in developing drug-screening systems for the treatment of CMT1. MATERIALS AND METHODS: To develop high-throughput screening (HTS) systems for CMT1, we generated cell models using transient expression of mutant proteins and chemical induction. RESULTS: Overexpression of wild type and mutant peripheral myelin protein 22 (PMP22) induced ER stress. Similar results were obtained from mutant myelin protein zero (MPZ) proteins. Protein localization revealed that expressed mutant PMP22 and MPZ proteins accumulated in the ER of Schwann cells. Overexpression of wild type and L16P mutant PMP22 also reduced cell viability, implying protein accumulation-mediated ER stress causes cell death. To develop more stable screening systems, we mimicked the ER stress-mediated cell death in Schwann cells using ER stress inducing chemicals. Thapsigargin treatment caused cell death via ER stress in a dose dependent manner, which was measured by expression of ER stress markers. CONCLUSION: We have developed genetically and chemically induced ER stress models using Schwann cells. Application of these models to HTS systems might facilitate the elucidation of molecular pathology and development of therapeutic options for CMT1.
Cell Death ; Cell Survival ; Charcot-Marie-Tooth Disease* ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Genotype ; Mass Screening* ; Mutant Proteins ; Myelin P0 Protein ; Myelin Sheath ; Pathology, Molecular ; Peripheral Nervous System Diseases ; Phenotype ; Schwann Cells ; Thapsigargin

Speech and language are uniquely human-specific traits, which contributed to humans becoming the predominant species on earth. Disruptions in the human speech and language function may result in diverse disorders. These include stuttering, aphasia, articulation disorder, spasmodic dysphonia, verbal dyspraxia, dyslexia and specific language impairment. Among these disorders, stuttering is the most common speech disorder characterized by disruptions in the normal flow of speech. Twin, adoption, and family studies have suggested that genetic factors are involved in susceptibility to stuttering. For several decades, multiple genetic studies including linkage analysis were performed to connect causative gene to stuttering, and several genetic studies have revealed the association of specific gene mutation with stuttering. One notable genetic discovery came from the genetic studies in the consanguineous Pakistani families. These studies suggested that mutations in the lysosomal enzyme-targeting pathway genes (GNPTAB, GNPTG and NAPGA) are associated with non-syndromic persistent stuttering. Although these studies have revealed some clues in understanding the genetic causes of stuttering, only a small fraction of patients are affected by these genes. In this study, we summarize recent advances and future challenges in an effort to understand genetic causes underlying stuttering.
Aphasia ; Apraxias ; Articulation Disorders ; Dyslexia ; Dysphonia ; Genetic Linkage ; Humans ; Lysosomes ; Stuttering*

Malformations of cortical development (MCD) cover a broad spectrum of developmental disorders which cause the various clinical manifestations including epilepsy, developmental delay, and intellectual disability. MCD have been clinically classified based on the disruption of developmental processes such as proliferation, migration, and organization. Molecular genetic studies of MCD have improved our understanding of these disorders at a molecular level beyond the clinical classification. These recent advances are resulted from the development of massive parallel sequencing technology, also known as next-generation sequencing (NGS), which has allowed researchers to uncover novel molecular genetic pathways associated with inherited or de novo mutations. Although an increasing number of disease-related genes or genetic variations have been identified, genotype-phenotype correlation is hampered when the biological or pathological functions of identified genetic variations are not fully understood. To elucidate the causality of genetic variations, in vivo disease models that reflect these variations are required. In the current review, we review the use of NGS technology to identify genes involved in MCD, and discuss how the functions of these identified genes can be validated through in vivo disease modeling.
Classification ; Disease Models, Animal ; Epilepsy ; Genetic Association Studies ; Genetic Variation ; Intellectual Disability ; Malformations of Cortical Development* ; Molecular Biology*