NANS-CDG: Expanding clinical insights with a novel patient with novel variants.

N-acetyl-d-neuraminic acid synthase-congenital disorder of glycosylation (NANS-CDG) is a rare autosomal recessive defect in the N-acetyl-neuraminic acid biosynthesis pathway. Herein, we report the first Korean NANS-CDG patient. A 10-year-old boy was referred to our clinic because of incidental radiographic findings indicating spondyloepimetaphyseal dysplasia. The patient had microcephaly, cavum septum pellucidum, and ventriculomegaly at birth, and at 10 years, a very short stature. He had a history of idiopathic chronic immune thrombocytopenia, central adrenal insufficiency, and hypothyroidism since infancy. The first unprovoked seizure occurred at the age of 2 years, and he was subsequently admitted to the hospital frequently because of respiratory infections and intractable seizures. Exome sequencing identified unreported biallelic variants of the NANS gene. Clinical and genetic confirmation of NANS-CDG highlights its expanding phenotypic and genotypic diversity.

The first case of novel variants of the FSHR mutation causing primary amenorrhea in 2 siblings in Korea.

Follicle-stimulating hormone receptor (FSHR) mutation is a rare cause of amenorrhea. We report the first case of FSHR mutations in Korea. Two female siblings, aged 16 (patient 1) and 19 (patient 2) years, were referred to the pediatric endocrinology clinic because of primary amenorrhea despite normal breast budding. Gonadotropin-releasing hormone stimulation test showed markedly elevated luteinizing hormone and follicle-stimulating hormone with a relatively low level of estrogen, suggesting hypergonadotropic hypogonadism. Pelvic magnetic resonance imaging revealed a bicornuate uterus in patient 1 and uterine hypoplasia with thinning of the endometrium in patient 2. The progesterone challenge test revealed no withdrawal of bleeding. After two months of administration of combined oral contraceptives, menarche was initiated at regular intervals. To determine the genetic cause of amenorrhea in these patients, whole exome sequencing (WES) was performed, which revealed a compound heterozygous FSHR mutation, c.1364T>G (p.Val455Gly) on exon 10, and c.374T>G (p.Leu125Arg) on exon 4; both of which were novel mutations and were confirmed by Sanger sequencing. The patients maintained regular menstruation and improved bone mineral density while taking combined oral contraceptives, calcium, and vitamin D. Therefore, FSHR mutations can be the cause of amenorrhea in Koreans, and WES facilitates diagnosing the rare cause of amenorrhea.

A phase II, multicenter, open-label trial to evaluate the safety and efficacy of ISU303 (Agalsidase beta) in patients with Fabry disease.

BACKGROUND: Fabry disease (FD) is caused by a deficiency in the activity of the lysosomal enzyme, α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (Gb3) deposition in multiple tissues. The current management of FD is enzyme replacement therapy (ERT). We report on the efficacy and safety of a new agalsidase beta, ISU303, in FD. METHODS: Ten patients (7 males, 3 females) were enrolled and administered a 1 mg/kg dose of ISU303, every other week for 6 months. The primary endpoint was the normalization of plasma Gb3 level. The secondary endpoints were the changes from baseline in urine Gb3 and the plasma and urine lyso-globotriaosylsphingosine (lyso-Gb3) level. Echocardiography, renal function test, and pain-related quality of life were also assessed before and after administration. Safety evaluation was performed including vital signs, laboratory tests, electrocardiograms, antibody screening tests, and adverse events at each visit. RESULTS: At 22 weeks of treatment, plasma and urine Gb3 level decreased by a mean of 4.01 ±â€…1.29 µg/mL (range 2.50-5.70) (P = .005) and 1.12 ±â€…1.98 µg/mg Cr. (range 0.04-5.65) (P = .017), respectively. However, no significant difference was observed in plasma and urine lyso-Gb3 levels. Echocardiography also was not changed. Renal function and pain-related quality of life showed improvements, but there was no clinical significance. No severe adverse events were observed. Only 1 patient developed an anti-drug antibody without neutralizing activity during the trial. CONCLUSION: This study showed the efficacy and safety of ISU303. Treatment with ISU303 significantly resulted in plasma and urine Gb3 decrease in patients with FD. These results suggest that ISU303 is safe and effective and can alternative ERT for FD.

Fabry nephropathy before and after enzyme replacement therapy: important role of renal biopsy in patients with Fabry disease.

BACKGROUND: In Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in patients with Fabry disease are limited. In the present study, the pathologic findings of patients with Fabry nephropathy receiving enzyme replacement therapy (ERT) and untreated patients without albuminuria were investigated. METHODS: The present study included 15 patients with Fabry disease who underwent renal biopsy while receiving ERT (group 1: n = 9, age 19-58 years, two males and seven females) or before ERT initiation (group 2: n = 6, age 11-66 years, one male and five females). All patients in group 2 were normoalbuminuric. RESULTS: Group 1 showed improved clinical symptoms, such as acroparesthesia. The ERT duration was 1.2 to 8 years and seven of the nine patients showed GL3 deposits in various kidney cells and segmental foot process effacement (FPE) of podocytes. GL3 deposits and FPE were not observed in the two remaining patients in group 1. Group 2 showed segmental FPE and podocyte GL3 deposits. Most patients in group 2 also showed GL3 deposits in the mesangium, endothelium, or tubular epithelium. CONCLUSION: The study results showed that segmental FPE and GL3 deposits can persist in Fabry nephropathy despite ERT. In addition, segmental FPE and GL3 deposits were observed in various kidney cells in normoalbuminuric patients with Fabry disease. These findings indicated that kidney biopsies at baseline and follow-up evaluation of Fabry nephropathy are essential for timely ERT initiation and ERT response assessment.

Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature.

BACKGROUND: Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). METHODS: Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018-2020 and evaluated by TES. RESULTS: For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were - 3.27 ± 1.25, - 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu-Cheney syndrome, Sheldon-Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). CONCLUSIONS: A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.

Genotype and clinical outcomes in children with congenital adrenal hyperplasia.

BACKGROUND: The study aimed to delineate the genotypic features and endocrine / metabolic profiles in patients with 21-hydroxylase deficiency. METHODS: Subjects were diagnosed with 21-hydroxylase deficiency by direct Sanger sequencing or multiple ligation-dependent probe amplification analysis and followed up in Pusan National University Children's Hospital from July 2008 to April 2019. The genotype, phenotype, and endocrine and metabolic profiles in children and young adults with congenital adrenal hyperplasia were investigated. RESULTS: Of a total of 33 patients, 16 (48.5%) were males. Median age was 7.4 years (range, 0.1-23.8 years). Thirty (90.9%) had salt-wasting phenotypes. Eleven (33.3%) initially presented with abnormality in a neonatal screening test without other symptoms. Among the 17 girls, seven received genital surgery. Sixty-five alleles from the 33 patients were evaluated. The distribution of CYP21A2 gene mutations revealed an intron 2 splice site (c.293-13A>G or c.293-13C>G) mutation as the most common one (22, 33.8%), followed by c.518T>A (10, 15.4%) and a large deletion / conversion (7, 10.8%), in order. One novel mutation was detected, c.332del(p.G111fs). Among the 27 patients aged >2 years, fifteen (55.6%) were obese / overweight, and ten (37.0%) needed growth hormone therapy due to short stature. Among the seven subjects aged >2 years and having high-risk genotype, five had impaired fasting glucose, three had precocious puberty, and four used growth hormone. A greater proportion of the high current corticosteroid dose group had impaired fasting glucose than in the low-dose group (64.3 vs 23.1%, P = 0.031). CONCLUSIONS: Early monitoring of endocrine and metabolic complications from childhood might benefit patients with congenital adrenal hyperplasia.

Clinical and molecular spectra of BRAF-associated RASopathy.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

Functional Characterization of Gomisin N in High-Fat-Induced Drosophila Obesity Models.

Gomisin N (GN) is lignin derived from Schisandra chinensis that has been reported to exhibit hepato-protective, anti-cancer, and anti-inflammatory effects. However, its role in whole-body energetic homeostasis remains unclear. In this study, we employed Drosophila melanogaster as a diet-induced obese model to elucidate the effects of GN on lipid and glucose metabolism by measuring climbing activity, triglyceride levels, and lifespan under a rearing condition of a high-fat diet (HFD) containing 20% coconut oil, with or without GN. Constant exposure of flies to an HFD resulted in increased body weight and decreased climbing activity, along with a shortened life span. Importantly, the administration of GN to HFD groups lowered their body weight and induced a specific upregulation of lipid storage droplet (Lsd)-2 and hormone-sensitive lipase (Hsl), in addition to improved lifespan. Importantly, GN in HFD groups appeared to downregulate heat shock protein Hsp90 family member (dGRP94), a key regulator of the endoplasmic reticulum stress response, which may also contribute to improved life span in the presence of GN. Taken together, these in vivo findings suggest that GN could serve as a useful agent for the prevention and treatment of obesity.

Clinical, endocrinological, and molecular features of four Korean cases of cytochrome P450 oxidoreductase deficiency.

PURPOSE: Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder caused by mutations in the POR gene encoding an electron donor for all microsomal P450 enzymes. It is characterized by adrenal insufficiency, ambiguous genitalia, maternal virilization during pregnancy, and skeletal dysplasia. In this study, we investigated the clinical, hormonal, and molecular characteristics of patients with POR deficiency in Korea. METHODS: This study included four patients with POR deficiency confirmed by biochemical and molecular analysis of POR. Clinical and biochemical findings were reviewed retrospectively. Mutation analysis of POR was performed by Sanger sequencing after polymerase chain reaction amplification of all coding exons and the exon-intron boundaries. RESULTS: All patients presented with adrenal insufficiency and ambiguous genitalia regardless of their genetic sex. Two patients harbored homozygous p.R457H mutations in POR and presented with adrenal insufficiency and genital ambiguity without skeletal phenotypes. The other two patients with compound heterozygous mutations of c.[1329_1330insC];[1370G>A] (p.[I444Hfs*6];[R457H]) manifested skeletal abnormalities, such as craniosynostosis and radiohumeral synostosis, suggesting Antley-Bixler syndrome. They also had multiple congenital anomalies involving heart, kidney, and hearing ability. All patients were treated with physiologic doses of oral hydrocortisone. CONCLUSION: We report the cases of 4 patients with POR deficiency identified by mutation analysis of POR. Although the study involved a small number of patients, the POR p.R457H mutation was the most common, suggesting founder effect in Korea. POR deficiency is rare and can be misdiagnosed as 21-hydroxylase or 17α-hydroxylase/17,20-lyase deficiency. Therefore, molecular analysis is critical for confirmatory diagnosis.

Identification of a Novel MYH9 Mutation in a Young Adult With Inherited Thrombocytopenia and Recurrent Seizures by Targeted Exome Sequencing.

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder caused by a mutation in the myosin heavy chain 9 (MYH9) gene. MHA patients have variable clinical manifestations including thrombocytopenia, renal injury, hearing impairment, and cataracts. We describe a 25-year-old man with isolated thrombocytopenia initially. He experienced recurrent seizures with stable thrombocytopenia after the first seizures related to intracranial hemorrhage. He was identified a novel c.3452C>T mutation by targeted exome sequencing. If a patient with thrombocytopenia shows recurrent seizures as well as renal, hearing, visual symptoms, MHA should be suspected and the targeted exome sequencing is considered an effective diagnostic tool.

A rare case of multiple pituitary adenomas in an adolescent Cushing disease presenting as a vertebral compression fracture.

Cushing disease in children and adolescents, especially with multiple pituitary adenomas (MPAs), is very rare. We report 17-year-old boy with MPAs. He presented with a vertebral compression fracture, weight gain, short stature, headache, and hypertension. On magnetic resonance imaging (MRI), only a left pituitary microadenoma was found. After surgery, transient clinical improvement was observed but headache and hypertension were observed again after 3 months later. Follow-up MRI showed a newly developed right pituitary microadenoma 6 months after the surgery. The need for careful clinical and radiographic follow-up should be emphasized in the search for potential MPAs in patients with persistent Cushing disease.

Determination of Autosomal Dominant or Recessive Methionine Adenosyltransferase I/III Deficiencies Based on Clinical and Molecular Studies.

Methionine adenosyltransferase (MAT) I/III deficiency can be inherited as autosomal dominant (AD) or as recessive (AR) traits in which mono- or biallelic MAT1A mutations have been identified, respectively. Although most patients have benign clinical outcomes, some with the AR form have neurological deficits. Here we describe 16 Korean patients with MAT I/III deficiency from 15 unrelated families identified by newborn screening. Ten probands had the AD MAT I/III deficiency, while six had AR MAT I/III deficiency. Plasma methionine (145.7 µmol/L versus 733.2 µmol/L, P < 0.05) and homocysteine levels (12.3 µmol/L versus 18.6 µmol/L, P < 0.05) were lower in the AD type than in AR type. In addition to the only reported AD MAT1A mutation, p.Arg264His, we identified two novel AD mutations, p.Arg249Gln and p.Gly280Arg. In the AR type, four previously reported and two novel mutations, p.Arg163Trp and p.Tyr335*, were identified. No exonic deletions were found by quantitative genomic polymerase chain reaction (PCR). Three-dimensional structural prediction programs indicated that the AD-type mutations were located on the dimer interface or in the substrate binding site, hindering MAT I/III dimerization or substrate binding, respectively, whereas the AR mutations were distant from the interface or substrate binding site. These results indicate that the AD or AR MAT I/III deficiency is correlated with clinical findings, substrate levels and structural features of the mutant proteins, which is important for the neurological management and genetic counseling of the patients.

Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease.

Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data.

Diverse genetic aetiologies and clinical outcomes of paediatric hypoparathyroidism.

CONTEXT: Hypoparathyroidism is characterized by hypocalcaemia, hyperphosphataemia, and low or inappropriately normal parathyroid hormone (PTH) levels. Idiopathic or genetic drivers are the predominant causes of hypoparathyroidism in paediatric-age patients. OBJECTIVE: This study investigated the aetiology and clinical course of primary hypoparathyroidism in infancy and childhood. SUBJECTS AND MEASUREMENTS: This study included 37 patients (23 males, 14 females) with primary hypoparathyroidism diagnosed prior to 18 years of age. We analysed aetiologies, initial presentation, age at diagnosis, endocrine and radiological findings, and outcomes. RESULTS: The median age at presentation was 1·7 months (range 1 day-17 years), and the mean follow-up duration was 7·0 ± 5·3 years (range 0·5-16·8 years). Our cohort included 22 cases (59·5%) of 22q11·2 microdeletion syndrome. Other aetiologies included hypoparathyroidism-deafness-renal dysplasia syndrome (5/37, 13·5%) and one patient each with autoimmune polyglandular syndrome type 1, Kearns-Sayre syndrome and Kenny-Caffey syndrome. The remaining 7 (18·9%) patients were classified as idiopathic hypoparathyroidism cases. Among the 15 patients who underwent brain imaging, 5 (33·3%) had basal ganglia calcification. Among the 26 patients examined by renal imaging, 5 (19·2%) had either nephrocalcinosis or a renal stone. After 11 months of calcium or calcitriol supplementation, 16 patients (43·2%) discontinued medication. The final PTH levels were significantly higher in patients with transient hypoparathyroidism than those with permanent hypoparathyroidism. CONCLUSIONS: Identification of the genetic aetiologies of hypoparathyroidism makes it possible to predict patient outcomes and provide appropriate genetic counselling. Long-term treatment with calcium and calcitriol necessitates monitoring for renal complications.

The first Korean case of HDR syndrome confirmed by clinical and molecular investigation.

Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare condition inherited as autosomal dominant trait and characterized by hypoparathyroidism, sensorineural deafness, and renal dysplasia. HDR syndrome is caused by haploinsufficiency of the GATA3 gene located on chromosome 10p15. Here, we report the case of a 32-day-old Korean male with HDR syndrome. He was presented due to repeated seizures over previous 3 days. The patient was born after 40 weeks of gestation with birth weight of 2930 g, and was the first-born baby of healthy Korean parents. Hypoparathyroidism was first noticed due to seizure. A multicystic left dysplastic kidney and vesicoureteral reflux were detected by ultrasound after birth. Auditory brainstem response (ABR) testing revealed that the patient had moderate sensorineural deafness, with hearing losses of 80 dB at the mid and higher frequencies for both ears. Echocardiography finding revealed secundum atrial septal deftect. Based on biochemical results and clinical findings, a presumptive diagnosis of HDR syndrome was made. GATA3 mutation analysis identified a heterozygous deletion, c.153del (p.Phe51Leufs*144) in exon 1 causing a frameshift mutation, which is a novel de novo mutation. Therefore, we suggest that HDR syndrome should be considered in the differential diagnosis in symptomatic or asymptomatic patients with hypoparathyroidism, and that renal ultrasound or ABR testing be performed to prevent a missed diagnosis. This is the first report on Korean patient with confirmed HDR syndrome with novel mutation.

Novel mutations and clinical outcomes of copper-histidine therapy in Menkes disease patients.

Menkes disease is a very rare X-linked copper metabolism disorder that results from an ATP7A gene mutation. With the advent of subcutaneous copper-histidine therapy, the early diagnosis of Menkes disease becomes of utmost importance for patients' prognosis. In the present study, the clinical characteristics of 12 Korean patients with Menkes disease (11 males and 1 female from 11 unrelated families) were described along with the mutation spectrum. Only 2 male patients were diagnosed in the neonatal period, and the other male patients were diagnosed at age 4.3 ± 1.9 months. The presenting signs included depigmented kinky hair, neurologic deficits, and hypotonia. Serum copper and ceruloplasmin levels were markedly decreased. Intracranial vessels were dilated with tortuosity and accompanied by regional cerebral infarctions, even at an early age. Of note, the female patient was diagnosed at age 18 months, during the evaluation for developmental delay, by characteristic MRA findings, biochemical profiles, and genetic evaluation. A total of 11 ATP7A mutations were identified, including five previously unreported mutations. Most mutations were truncated (except 1 missense mutation), including 3 frameshift, 2 nonsense, 3 large deletion, and 2 splice-site variants. The age at commencement of copper-histidine treatment was variable among patients age 7.3 ± 7.5 (0.5-27) months. Despite the treatment, seven patients died before age 5 years, and the remaining patients were severely retarded in neurodevelopment. The poor outcomes of our patients might be related to delayed therapy, but severe ATP7A mutations should be noted as well.

Neurofibromatosis type 1: a single center's experience in Korea.

PURPOSE: Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by an NF1 gene mutation. NF1 is also a multisystem disorder that primarily affects the skin and nervous system. The goal of this study was to delineate the phenotypic characterization and assess the NF1 mutational spectrum in patients with NF1. METHODS: A total of 42 patients, 14 females and 28 males, were enrolled in this study. Clinical manifestations and results of the genetic study were retrospectively reviewed. RESULTS: Age of the patients at the time of NF1 diagnosis was 15.8±14.6 years (range, 1-62 years). Twelve patients (28.6%) had a family history of NF1. Among the 42 patients, Café-au-lait spots were shown in 42 (100%), neurofibroma in 31 (73.8%), freckling in 22 (52.4%), and Lisch nodules in seven (16.7%). The most common abnormal finding in the brain was hamartoma (20%). Mental retardation was observed in five patients (11.9%), seizures in one patient (2.4%), and plexiform neurofibromas (PNFs) in four patients (9.5%). One patient with PNFs died due to a malignant peripheral nerve sheath tumor in the chest cavity. Genetic analysis of seven patients identified six single base substitutions (three missense and three nonsense) and one small deletion. Among these mutations, five (71.4%) were novel (two missense mutations: p.Leu1773Pro, p.His1170Leu; two nonsense mutations: p.Arg2517(*), p.Cys2371(*); one small deletion: p.Leu1944Phefs(*)6). CONCLUSION: The clinical characteristics of 42 Korean patients with NF1 were extremely variable and the mutations of the NF1 gene were genetically heterogeneous with a high mutation-detection rate.

A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.

KBG syndrome is a very rare genetic disorder characterized by macrodontia of upper central incisors, global developmental delay, distinctive craniofacial features, short stature, and skeletal anomalies. Ankyrin repeat domain 11 gene (ANKRD11) has recently been identified as a causal factor of this syndrome. We describe a 6-yr-old Korean boy with features of KBG syndrome. The patient had a short stature, macrodontia, dysmorphic facial features, speech and motor delay with intellectual disability, and partial seizures as indicated by the electroencephalogram, but he was neither autistic nor had autism spectrum disorders. Using high-resolution oligonucleotide array comparative genomic hybridization, we identified a heterozygous 240-kb deletion at 16q24.3 corresponding to ANKRD11. This patient provided additional evidence on the influence of ANKRD11 in KBG syndrome and suggested that deletion limited to ANKRD11 is unlikely to cause autism.

Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome.

Kabuki syndrome (KS) (OMIM#147920) is a multiple congenital anomaly/mental retardation syndrome. Recently, pathogenic variants in KMT2D and KDM6A were identified as the causes of KS in 55.8-80.0% of patients. To elucidate further the molecular characteristics of Korean patients with KS, we screened a cohort of patients with clinically defined KS for mutations in KMT2D and KDM6A. Whole-exome sequencing and direct sequencing for validation were performed in 12 patients with a clinical suspicion of KS. KMT2D and KDM6A mutations were identified in 11 (91.7%) patients. No recurrent mutation was observed, and 10 out of the 11 mutations found were novel. KMT2D mutations were detected in 10 patients, including four small deletions or insertions and four nonsense and two missense mutations. One girl had a novel splice-site mutation in KDM6A. Each patient had a unique individual mutation. This is the first report of mutational analysis via exome sequencing in Korean patients with KS. Because the mutation-detection rate was high in this study, rigorous mutation analysis of KMT2D and KDM6A may be an important tool for the early diagnosis and genetic counseling of Korean patients with KS.