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A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Recent molecular genetic studies have revealed that Schimmelpenning-Feuerstein-Mims syndrome (SFMS), which presents as sebaceous nevi, is a mosaic RASopathy caused by postzygotic somatic activating mutations in HRAS , NRAS , or KRAS Some patients with SFMS also have hypophosphatemic rickets, called cutaneous skeletal hypophosphatemia syndrome (CSHS). We here report a pediatric case of biopsy-proven CSHS with mosaic mutation in the HRAS gene. A girl who showed extensive nevus sebaceous since birth had suffered progressive lower extremity deformity since the age of 5 years. We found hypophosphatemic rickets in laboratory and radiological studies. From the molecular study with skin tissue with nevus sebaceous, we identified a heterozygous mutation, c.182A>G (p.Gln61Arg), in exon 3 of HRAS by Sanger sequencing. However, we did not find this mutation in the peripheral blood and unaffected tissue, which demonstrated mosaic distribution of the mutation throughout the body. Given the rarity of the previous genetically proven CSHS cases, accumulation of more cases is needed to establish the role of Ras activation in skeletal manifestations in CSHS, which is likely due to excessive production of fibroblast growth factor 23., (© 2018 by the Association of Clinical Scientists, Inc.)

Argininosuccinic aciduria (ASA), which is considered to be the second most common urea cycle disorder (UCD), is caused by an argininosuccinate lyase deficiency and is biochemically characterized by elevation of argininosuccinic acid and arginine deficiency. In addition to hyperammonemia, other characteristic features of ASA include hepatic fibrosis, hypertension, neurocognitive deficiencies, and trichorrhexis nodosa. Herein, we retrospectively reviewed the clinical findings, biochemical profiles, and genotypic characteristics of five Korean patients with ASA, who showed typical phenotypes and biochemical findings of the disease. Molecular analysis of these patients revealed six novel ASL mutations. Next, we investigated the prevalence of all types of UCDs in Korea. Of note, over a two decade periods, ASA was only detected in 6.3% of patients with a UCD, which made it the fourth most common UCD in Korea. In comparison with Caucasians, in whom ASA is the second most common UCD, ASA is comparatively rare in East Asian populations, including Japanese and Koreans. These findings suggest the possibility of geographic variation in UCDs among ethnic groups.

Desmoplakin is an essential cytoplasmic plaque protein in desmosomes, and it is the major linker between intercellular junctions in the skin and heart. The role of desmoplakin is anchoring transmembrane cadherins to cytoplasmic intermediate filaments. The desmoplakin gene ( DSP ) is located on chromosome 6, and six common allelic disorders are associated with this gene, including autosomal-dominant or -recessive disorders that affect the skin, heart, hair, and nails. In particular, lethal acantholytic epidermolysis bullosa (LAEB) is an autosomal recessively inherited and extremely rare genetic skin disorder, and only three molecularly confirmed families with LAEB have been reported previously. Generalized oozing erosion of the entire skin is the main clinical feature, which leads to excessive transcutaneous fluid loss and neonatal death. Histopathologically, this disorder is classified as a suprabasal subtype of epidermolysis bullosa simplex. In this study, we report for the first time in Korea on monozygotic twins with LAEB caused by two novel nonsense mutations in the DSP gene. Both of the twins exhibited severe and rapid progressive whole body skin erosion, and they died shortly after birth because of multiorgan failure followed by excessive fluid loss., (© 2017 by the Association of Clinical Scientists, Inc.)

Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD; OMIM#201475) is a rare metabolic disorder of mitochondrial fatty acid oxidation. VLCADD includes three clinical forms that are grouped based on disease severity. Here, we present two unrelated patients suspected of having VLCADD based on a newborn screening test. One patient was diagnosed in the neonatal period and, to date, has not shown any symptoms or signs associated with VLCADD; in contrast, diagnosis was delayed in the other patient after events of hypoketotic hypoglycemia and steatohepatitis. Repeated biochemical analyses and a liver biopsy implied VLCADD, and direct sequencing analysis led to the discovery of three novel mutations, including an identical missense variant (p.Ser207Pro) on ACADVL. Our patients were the first cases of the milder form of VLCADD, and the identical mutation detected might represent a founder mutation in the Korean population and be associated with the milder phenotype of VLCADD., (© 2016 by the Association of Clinical Scientists, Inc.)

Craniofrontonasal syndrome (CFNS) is a very rare genetic disorder with variable clinical phenotypes, including brachycephaly, hypertelorism, and a bifid nasal tip. Moreover, longitudinal splittings of the nails and skeletal abnormalities may accompany this condition. CFNS is inherited in an X-linked dominant manner; however, affected heterozygous females exhibit additional and more severe manifestations compared with affected hemizygous males, paradoxically. Here, we report for the first time in Korea two girls with molecularly confirmed CFNS. They commonly showed the typical craniofacial manifestations of CFNS, whereas the severity and the type of associated anomalies differed between them, suggesting phenotypic diversity for this disease. One patient showed unilateral coronal synostosis, cleft palate, and septate uterus together with intellectual disability. The other patient exhibited bilateral coronal synostosis and normal developmental milestones, without anomalies in other organs. A Sanger sequencing analysis of these patients revealed one novel (IVS2+3G>T) and one previously reported mutation (p.Gly151Ser) in EFNB1 Both patients were de novo cases without a family history of CFNS., (© 2016 by the Association of Clinical Scientists, Inc.)

Short-chain acyl-CoA dehydrogenase (SCAD) catalyzes the first step in mitochondrial short-chain β-oxidation, and its deficiency is caused by mutations in the ACADS We sought to investigate the spectrum ACADS mutations and associated clinical manifestations in Korean patients with SCAD deficiency. The study included ten patients with SCAD deficiency from 8 unrelated families as diagnosed by biochemical profile and mutation analyses. Clinical features, biochemical data, growth, and neurodevelopmental state were reviewed retrospectively. Eight patients were found during newborn screening, and two were diagnosed by family screening. During follow-up ranging from 2 months to 4.5 years, no hypoglycemic event was noted, and the development and growth of the patients were normal, except in two siblings. One exhibited hypotonia and gross motor delay, while one girl showed cyclic vomiting until the age of two years. We identified seven different mutations of ACADS Of these, p.E344G was the most frequent mutation with an allele frequency of 50%, followed by p.P55L with 18.8%. p.G108D and four novel mutations were identified: p.L93I, p.E228K, p.P377L, and p.R386H. Korean patients with SCAD deficiency showed heterogenous clinical features and ACADS genotype. Our data contributes to a better understanding of the distinct molecular genetic characteristics and clinical manifestations of SCAD deficiency., (© 2016 by the Association of Clinical Scientists, Inc.)

SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis, which is caused by biallelic mutations in the POC1A gene. Only 19 patients with mutation-confirmed SOFT syndrome have been reported to date, all of whom carried homozygous variants that were strongly associated with consanguineous marriages. We report an 8.5-year-old boy with SOFT syndrome showing primordial dwarfism, no effect of growth-hormone therapy and skeletal dysplasia. This is the first report of compound heterozygous variants in POC1A, one previously reported and the other novel. A characteristic skeletal manifestation is reported.

Carnitine palmitoyltransferase 1A (CPT1A) is an enzyme functioning in mitochondrial fatty acid oxidation (FAO) of the liver. Patients with CPT1A deficiency have impaired mitochondrial FAO and display hypoketotic hypoglycemia and hepatic encephalopathy as typical manifestations. In this report, we present a case of CPT1A deficiency presenting jaundice as the first manifestation. A 1.9 years old boy showed jaundice and elevated levels of free and total carnitine were observed. From direct sequencing analysis of CPT1A, two novel mutations, c.1163+1G>A and c.1393G>A (p.Gly465Arg), were identified. At the age of 2.2 years, hypoglycemia, tachycardia, and altered mental status developed just after cranioplasty for craniosynostosis. High glucose infusion rate was required for recovery of his vital signs and mentality. Diet rich in high carbohydrate, low fat and inclusion of medium chain triglyceride oil resulted in improvement in cholestatic hepatitis and since then the boy has shown normal growth velocity and developmental milestones to date.

CHARGE syndrome (OMIM 214800) is a rare autosomal-dominant congenital malformation syndrome that results from haploinsufficiency of the chromodomain helicase DNA-binding protein 7 (CHD7). We performed a phenotypic characterization and genetic analysis of CHD7 in 18 Korean patients with CHARGE syndrome. Eighteen unrelated Korean patients (10 females and 8 males; age range 0.0-19.6 years) with CHARGE syndrome were enrolled. Clinical data were collected by retrospective review of medical records. A serial analysis via sequencing and multiple ligation-dependent probe amplification of CHD7 was performed to determine the molecular genetic spectrum of the patients. The prevalence of cardinal symptoms was as follows: coloboma (13/18, 72.2%), heart defects (13/18, 72.2%), choanal atresia/stenosis (4/18, 22.2%), retarded growth (10/18, 55.6%), genital anomalies (15/18, 83.3%) and ear abnormalities (18/18, 100%). Five patients had cerebellar vermis hypoplasia (5/17, 29.4%) with no clinical symptoms or signs of cerebellar dysfunction. Furthermore, we identified genetic alterations in all 18 patients, including 10 novel mutations. Considering its frequency among patients with CHD7 mutations, cerebellar vermis hypoplasia may be a clinical diagnostic clue of CHARGE syndrome, although it is not included in the diagnostic criteria. And, the identification of CHD7 mutations may help the confirmative diagnosis.

Hajdu-Cheney syndrome (HCS) and serpentine fibula-polycystic kidney syndrome (SFPKS) share many similarities, including craniofacial abnormalities, bony deformities, and renal involvement. Because mutations in exon 34 of NOTCH2 have been identified recently in both HCS and SFPKS patients, it has been suggested that these two syndromes be classed as the same disorder. A 3-year-old boy presented with polycystic kidneys and club feet detected during the fetal period; however, acroosteolysis and curved fibulae were not observed. His mother showed osteoporosis and had a history of compression fractures in the spine without renal anomalies. Although the same novel mutation in NOTCH2 was found in both the mother and her son, these patients displayed different clinical manifestations. In this report, we present a familial case of HCS in a boy and his mother that was suspected on physical examination and radiological findings. We speculate that HCS and SFPKS are a single disease entity with a wide spectrum of clinical manifestations associated with truncating mutations in exon 34 of NOTCH2., (© 2015 by the Association of Clinical Scientists, Inc.)

Chromosomal translocation of 2q37.1 just distal to the NPPC gene coding for C-type natriuretic peptide (CNP) and subsequent overproduction of CNP have been reported to cause a skeletal overgrowth syndrome. Loeys-Dietz syndrome (LDS) is one of marfanoid overgrowth syndromes, of which subtype IV is caused by haploinsufficiency of transforming growth factor beta 2 (TGFB2). We report on a girl with clinical phenotypes of overgrowth syndrome, including long and slim body habitus, macrodactyly of the big toe, scoliosis, ankle valgus deformity, coxa valga, slipped capital femoral epiphysis, and aortic root dilatation. Karyotyping revealed a balanced chromosomal translocation between 1q41 and 2q37.1, and the breakpoints could be mapped by targeted resequencing analysis. On chromosome 2q37.1, the translocation took place 200,365 bp downstream of NPPC, and serum level of the amino terminal of CNP was elevated. The contralateral site of translocation on chromosome 1q41 disrupted TGFB2 gene, presumed to cause its haploinsufficiency. This case supports the concept that NPPC is overexpressed because of the loss of a specific negative regulatory control in the normal chromosomal location, and demonstrates the effectiveness of targeted resequencing in the mapping of breakpoints., (© 2015 Wiley Periodicals, Inc.)

Unlabelled: Monochorionic (MC) pregnancy in humans is usually considered to be associated only with monozygotic twinning. However, several reports have revealed that dizygotic (DZ) twins can also share a chorion during pregnancy. A chimera is defined as an organism that contains different cells derived from two or more distinct zygotes. As artificial reproductive techniques develop, it can be predicted that the occurrence of MC DZ twins will increase, and DNA-fingerprinting methods, such as short tandem repeat (STR) analysis, will be essential for their accurate diagnosis. We report the first Korean case of MC DZ twins with blood chimerism, 46,XX/46,XY, as a consequence of in vitro fertilization/embryo transfer. The clinical phenotypes of the twins' genitalia were complete female and male, respectively. Monochorionicity was confirmed by pathological analysis of the placenta after delivery. The dizygosity and confined blood chimerism of the twins were confirmed by STR analysis using their peripheral lymphocytes and skin fibroblasts. The confined blood chimerism of the twins can be considered similar to the status of the hematopoietic system in patients after allogenic bone marrow transplantation., Conclusion: When MC twins with discordant sex are expected during pregnancy, it is important to consider the possibility of DZ twins showing normal sexual development, especially in twins who were fertilized using artificial reproductive techniques.

Sotos syndrome (SS) is a congenital overgrowth syndrome. NSD1 mutations are identifiable in most SS patients. There have been a few reports of familial inheritance of SS worldwide, but no familial cases have been reported in Korea. A 6-month-old girl had tall stature and macrocephaly with mild ventricular enlargement, and showed mild delay in motor and language development. Her mother also had tall stature and a long narrow face. The baby and her mother were suspected of having familial SS. Chromosome 5q35 microdeletion was first ruled out by fluorescence in situ hybridization analysis, and direct sequencing of NSD1 revealed a novel heterozygous mutation in exon 22 (c.6356delA; p.Asp2119Valfs*31). This report describes, for the first time, a Korean family with two generations of SS resulting from a novel intragenic NSD1 mutation.

Langer-Giedion syndrome (LGS; MIM 150230), also called trichorhinophalangeal syndrome type II (TRPS2), is a contiguous gene syndrome caused by a one-copy deletion in the chromosome 8q23-q24 region, spanning the genes TRPS1 and EXT1. We identified an LGS family with two affected and two unaffected siblings from unaffected parents. To investigate the etiology of recurrence of LGS in this family, array CGH was performed on all family members. We identified a 7.29 Mb interstitial deletion at chromosome region 8q23-q24 in the two affected siblings, but no such deletion in the unaffected family members. However, the mother and one of the two unaffected siblings carried a 1.29 Mb deletion at chromosome region 8q24.1, sharing the distal breakpoint with the larger deleted segment found in the affected siblings. Another unaffected sibling had a 6.0 Mb duplication, sharing the proximal breakpoint of the deletion in the affected siblings. Karyotypic and FISH analyses in the unaffected mother revealed an insertional translocation of 8q23-q24 genomic material into chromosome 13: 46,XX,ins(13;8)(q33;q23q24). This insertional translocation in the mother results in the recurrence of LGS in this family, highlighting the importance of submicroscopic rearrangements in the genetic counseling for LGS., (Copyright © 2013. Published by Elsevier Masson SAS.)

Monozygotic twins, developed from a single zygote, are almost identical in clinical phenotype and concordant karyotypes. Monozygotic twins with discordant karyotypes are thought to be quite rare. Here, we report monochorionic-diamniotic twins discordant for Down syndrome. On findings of prenatal ultrasonography, nuchal translucency thickness was different between twins, and suggested that one of the twins was at high risk for having chromosomal abnormalities including Down syndrome. The twins were monochorionic-diamniotic; therefore, chorionic villi sampling of the common placenta was performed. The karyotype of the chorionic villi cells was 46,XX, and pregnancy was maintained. After delivery, dysmorphic clinical features suggesting Down syndrome were found in one of the twins, while the other twin showed a morphologically normal appearance. Karyotypes of peripheral blood leukocytes were repeatedly normal in the dysmorphic twin; however, the karyotype of skin fibroblasts from the dysmorphic twin indicated Down syndrome mosaicism; 47,XX,+21[99]/46,XX[2]. The karyotype of skin fibroblasts from the morphologically normal twin was 46,XX. Monozygosity of the twins was confirmed by a short tandem repeat analysis using 16 polymorphic markers. A mitotic nondisjunction followed by the twinning would explain the discordant karyotypes between monozygotic twins.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations of the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of pseudogenes, and the great variety of mutations. Also, few probable genotype-phenotype correlations have been found in NF1. In this study 78 Korean patients from 60 families were screened for NF1 mutations. Mutation analysis of the entire coding region and flanking splice sites was carried out and included the use of a combination of reverse transcription polymerase chain reaction, multiplex ligation probe amplification, or fluorescence in situ hybridization. Mutation spectrum and genotype-phenotype relationship were assessed. Fifty-two distinct NF1 mutations were identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense), 11 missplicing mutations, seven small insertion or deletions, and four gross deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were recurrently identified. The mutations were evenly distributed across exon 1 through intron 47 of NF1, and no mutational hot spots were found. A genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. As technologies advance in molecular genetics, the mutation detection rate will increase. Considering that 30.8% of detected mutations were novel, exhaustive mutation analysis of NF1 may be an important tool in early diagnosis and genetic counseling., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Schinzel-Giedion syndrome (SGS) is a rare multiple congenital malformation syndrome defined by characteristic facial features, profound developmental delay, severe growth failure, and multiple congenital anomalies. Most individuals affected by SGS die in early childhood mainly because of progressive neurodegeneration and respiratory failure. The causative gene of SGS, SETBP1, was identified, but there are few reports of SGS with molecular confirmation worldwide., Patient and Method: In this study, we present a 10-month-old boy presenting with SGS complicated by epilepsy and profound developmental delay., Results: Typical facial features, multiple anomalies, and associated neurological findings suggested a clinical diagnosis of SGS. Unusually in our patient, generalized tonic seizure occurred and has been controlled well by combined antiepileptic therapy during 7 months of follow-up. Electroencephalography findings were compatible with partial seizures, and ventriculomegaly, thinning of the corpus callosum, and delayed myelination were identified on brain MR images. SETBP1 mutational analysis revealed the presence of a recurrent mutation, p.Gly870Ser. Thus, the diagnosis of our patient was molecularly confirmed as SGS., Conclusions: Although this syndrome is extremely rare, it is important to consider SGS in the differential diagnosis of infantile-onset epilepsy with progressive neurodevelopmental retardation, especially in patients with multiple anomalies and facial dysmorphism.

Sotos syndrome is an overgrowth syndrome with characteristic facial dysmorphism, variable severity of learning disabilities and macrocephaly with overgrowth. Haploinsufficiency of the nuclear receptor SET domain-containing protein 1 (NSD1) gene located on 5q35 has been implicated as the cause of Sotos syndrome. This study was performed to investigate the mutation spectrum of NSD1 abnormalities and meaningful genotype-phenotype correlations in Korean patients with Sotos syndrome. Eighteen unrelated Korean patients with Sotos syndrome were enrolled for clinical and molecular analyses. Cytogenetic studies were performed to confirm 5q35 microdeletion, and NSD1 sequencing analysis was performed to identify intragenic mutations. NSD1 abnormalities were identified in 15 (83%) patients. Among them, eight patients (53%) had 5q35 microdeletions and the other seven patients (47%) had seven different NSD1 intragenic mutations including four novel mutations. The mutation spectrum of Korean patients with Sotos syndrome was similar to that of previous studies for Japanese patients. Height was significantly shorter and age of walking alone was significantly older in the microdeletion group compared with those in the intragenic mutation group. No significant differences were observed for other clinical characteristics between the microdeletion and intragenic mutation groups. Further studies with a larger number of patients will be necessary to draw conclusive genotype-phenotype correlations.

Background: This study was undertaken to evaluate the association of the E23K polymorphism of KCNJ11 and type 1 diabetes in a Korean population., Methods: Clinical variables from 70 Korean children with type 1 diabetes were analyzed. Patients' DNA was screened for the E23 locus in the KCNJ11 gene. Each genotype frequency and clinical characteristics according to the genotypes were compared between the patient and control groups., Results: The genotype frequencies of the KCNJ11 E23 polymorphic locus in the patient group were 30.0% for EE, 44.3% for EK, and 25.7% for KK. We detected no differences in genotype frequencies between the patient and control groups. Additionally, in the patient group, no difference was detected in the clinical phenotypes among the three genotypes., Conclusion: Although a rather small sample size constituted a limitation of this study, the association of the E23K polymorphism with type 1 diabetes was not statistically significant in the Korean population evaluated.

The clinical spectrum of holoprosencephaly is broad, and its etiology is heterogeneous. To investigate the clinical spectrum of holoprosencephaly in Korea, we performed a database analysis of 55 cases of holoprosencephaly, including 12 diagnosed postnatally, all from a single institution. The 55 patients were categorized into several types: 37 alobar, eight semilobar, eight lobar, and two middle interhemispheric variant. Associated brain (41.8%) and craniofacial (74.5%) features varied substantially. Of 40 patients studied according to karyotype, chromosomal aberrations were detected in 18 (45.0%). Twenty-seven (49.1%) patients, diagnosed postnatally, exhibited milder types of holoprosencephaly and less profound craniofacial malformations than in prenatal diagnoses. Moreover, in postnatally diagnosed patients, the subgroup surviving longer than 1 month also exhibited a milder holoprosencephaly type and lower incidence of associated craniofacial malformations. The most frequent clinical signs in living children with holoprosencephaly included microcephaly, global developmental delay, and seizures. Holoprosencephaly represents a heterogeneous entity with different clinical manifestations and etiologies. A high index of suspicion, coupled with appropriate imaging studies, can enable accurate diagnoses and prognoses of holoprosencephaly., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: Previous studies have reported the effects of parental origin of the X chromosome on specific phenotypic and cognitive profiles in Turner syndrome (TS). Here, we investigate the possible parent-of-origin effects on physical phenotypes and responsiveness to GH in Korean patients with TS., Design and Patients: Thirty-three patients with TS with nonmosaic karyotype and their parents participated in this study. The parental origin of the normal X chromosome was determined by comparing parental DNA polymorphisms using nine highly polymorphic microsatellite markers on the X chromosome. For the evaluation of parent-of-origin effects, typical phenotypic traits, including congenital malformations, auxological and endocrinological profiles, were compared., Results: The retained X chromosome was of maternal (X(m)) origin in 60.6% patients and paternal (X(p)) origin in 39.4% patients. No significant parent-of-origin effects on stature, body mass index, cardiac, renal, skeletal, lymphatic, hearing or ocular systems were evident. We observed no differences in height gain after GH treatment. In patients with the 45,X karyotype, patient height was positively correlated with maternal height in the X(m) group (r = 0.60, P = 0.04). Moreover, patient height was more significantly correlated with maternal than paternal height, irrespective of the parental origin of the retained X chromosome., Conclusion: While we observed no significant impact of parental origin of the X chromosome on several phenotypic traits in patients with TS, a maternal imprinting effect on stature was suggested at least in patients with 45,X. Further studies on a larger number of patients with TS are essential to define the potential imprinting effects of undetermined genes on the X chromosome.

Objective: Recombinant human growth hormone (GH) can achieve final adult height gain in girls with Turner syndrome (TS), but its efficacy varies widely across individuals. The exon 3-deleted polymorphism of growth hormone receptor (d3-GHR) has been reported to be associated with responsiveness to GH therapy. The short-term growth response of Turner patients to GH therapy was analysed according to their GHR-exon 3 polymorphism genotype., Design and Patients: This was a retrospective study of 175 TS patients. Auxological and endocrine parameters were measured, and the GHR-exon 3 genotype was analysed. Allelic frequencies of GHR-exon 3 genotype were compared between patients with TS and control individuals. GH had been administered to 147 patients, 115 of which remained pre-pubertal after the first follow-up year. Changes in height standard deviation score (SDS), height velocity (HV), body mass index (BMI), IGF-1 and IGF binding protein-3 (IGFBP-3) concentrations were compared between these patients, grouped according to genotype, after the first follow-up year., Results: There was no difference in GHR-exon 3 genotype frequency between the TS and control groups of Koreans. According to the GHR-exon 3 genotype (fl/fl group vs. d3/fl and d3/d3 group), HV gain and height SDS gain did not differ significantly at the first year of GH therapy. Moreover, changes in IGF-1, IGFBP-3 concentration and BMI showed no significant difference between the groups with and without d3-GHR after 1 year of GH therapy., Conclusion: The distribution of the GHR-exon 3 genotype was similar in the TS and control groups in a Korean population. The growth promotion efficacy of GH therapy did not differ significantly between TS patients with and without the d3-GHR allele. These findings indicate that the GHR-exon 3 genotype may not be a major factor to affect the GH response in Korean Turner patients.

Objective: A human GH receptor (GHR) gene exon 3 polymorphism (d3-GHR) has been reported to be associated with responsiveness to GH therapy. We assessed the frequencies of this polymorphism in Korean control and idiopathic short stature (ISS) populations, and analysed short-term growth response to GH therapy according to GHR-exon 3 genotypes in Korean children with ISS., Design and Patients: This was a retrospective study in 158 ISS children. Auxological and endocrine parameters were measured, and the GHR-exon 3 genotype was analysed. Allelic frequencies of GHR-exon 3 genotype were compared between the ISS group and a control group. GH had been administered for 62 patients, 52 of whom remained prepubertal after the first follow-up year. Changes in height velocity (HV) and IGF-1 and IGFBP-3 concentrations following GH therapy were compared in patients with these genotypes., Results: There was no difference in GHR-exon 3 genotype frequency between ISS and control groups of Koreans. However, the fl/fl genotype was more frequent in Koreans than in Caucasians. ISS children with d3-GHR showed a significantly higher increment in HV (P = 0.002) and a marginally significant increment in IGF-1 concentration (P = 0.064) at the first year of GH therapy., Conclusion: fl-GHR was more frequently detected in a Korean population than in Caucasians. The growth promotion efficacy of GH therapy differed significantly between ISS patients with and without the d3-GHR allele. These findings indicate that the GHR-exon 3 polymorphism can affect the growth promoting efficacy of short-term GH therapy in Korean children with ISS.

After 2006, germline mutations in the KRAS, SOS1, and RAF1 genes were reported to cause Noonan syndrome (NS), in addition to the PTPN11 gene, and now we can find the etiology of disease in approximately 60-70% of NS cases. The aim of this study was to assess the correlation between phenotype and genotype by molecular analysis of the PTPN11, SOS1, KRAS, and RAF1 genes in 59 Korean patients with NS. We found disease-causing mutations in 30 (50.8%) patients, which were located in the PTPN11 (27.1%), SOS1 (16.9%), KRAS (1.7%), and RAF1 (5.1%) genes. Three novel mutations (T59A in PTPN11, K170E in SOS1, S259T in RAF1) were identified. The patients with PTPN11 mutations showed higher prevalences of patent ductus arteriosus and thrombocytopenia. The patients with SOS1 mutations had a lower prevalence of delayed psychomotor development. All patients with RAF1 mutations had hypertrophic cardiomyopathy. Typical facial features and auxological parameters were, on statistical analysis, not significantly different between the groups. The molecular defects of NS are genetically heterogeneous and involve several genes other than PTPN11 related to the RAS-MAPK pathway.

Citrin deficiency resulting from mutations of the SLC25A13 gene is associated with two major clinical phenotypes; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type 2 citrullinemia (CTLN2). In Korea, 6 cases of citrin deficiency were diagnosed based on biochemical and molecular findings. Four NICCD patients (2 boys and 2 girls) presented high citrulline levels on a newborn screening test or neonatal cholestasis. They were associated with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminemia, mild hyperammonemia, elevated citrulline, methionine and threonine. All of the hepatic manifestations were resolved spontaneously at the age of 5-9 months. Mutation analysis identified them as compound heterozygotes carrying each of the c.851del4, IVS11+1G>A, IVS13+1G>A, G393S, and IVS16ins3kb mutant alleles. Two adult male CTLN2 patients were identified. They were aged 24 and 37 years, and presented sudden loss of consciousness, hyperammonemia and citrullinemia. They were compound heterozygotes with IVS13+1G>A and IVS16ins3kb, and with c.851del4 and IVS11+1G>A mutant alleles. This report describes the clinical characteristics, biochemical findings and molecular analysis of the SLC25A13 gene of patients with citrin deficiency in Korea.