Genetic profiling and diagnostic strategies for patients with ectodermal dysplasias in Korea.

BACKGROUND: Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer. RESULTS: In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations. CONCLUSIONS: When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.

Two families with spondylo-epi-metaphyseal dysplasia due to compound heterozygocity in the vWFA domain of MATN3.

Heterozygous variants of MATN3 is one of the common causes of multiple epiphyseal dysplasia (MED). Here we report three individuals from two unrelated families who harbor compound heterozygous variants in MATN3 (p.Arg121Trp and p.Val220Ala). Contrary to the MED phenotype, these individuals exhibit spondyloepimetaphyseal dysplasia (SEMD) resembling the phenotypes caused by homozygous MATN3 variants. Clinical manifestations included short stature, aggravating genu varum, joint laxity, and spinal abnormalities. Radiographic findings were distinct from typical MED. These compound heterozygous variants in the von Willebrand factor A domain of MATN3 expand the phenotypic spectrum associated with MATN3, and suggest that extreme MATN3 dysfunction resulting from dual variants can lead to a specific pattern of SEMD.

Dramatic Clinical Improvement With Biotin Mega-Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency.

INTRODUCTION: Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle. Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death. METHODS AND RESULTS: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation. Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis. Genetic analysis of actionable metabolic disorders revealed compound heterozygous variants of HLCS (NM_000411.8), specifically c.[710T>C (p.Leu237Pro)]; [1544G>A (p.Ser515Asn)], prompting the initiation of biotin mega-dose therapy (10 mg/day). Remarkably, dramatic clinical improvement in lactic acidosis was observed the day after initiating biotin administration, leading to the discontinuation of mechanical ventilation within 6 days. The patient remained in stable condition during follow-up, exhibiting normal growth and development along with consistently stable laboratory findings up to 18 months of age. CONCLUSION: Our case highlights the significance of early genetic testing in neonates with unexplained metabolic disorders to enable timely diagnosis and therapy initiation. Biotin therapy has demonstrated remarkable efficacy in improving the clinical condition of patients with HLCS deficiency, leading to favorable outcomes.

Challenges in endoscopic third ventriculostomy for patients with achondroplasia: a focus on third ventricle floor anatomy.

OBJECTIVE: Hydrocephalus is one of the neurological risks occurring in patients with achondroplasia. Ventriculoperitoneal shunt (VPS) insertion is the most common treatment. However, reports of successful endoscopic third ventriculostomy (ETV) suggest that ETV may be a good alternative to VPS insertion in achondroplasia. However, it has been stated that ETV in achondroplasia patients is technically demanding to perform. The current study examined the anatomical variations of the third ventricle and the brainstem in achondroplasia patients and correlated the findings with the difficulty of performing ETV. METHODS: A retrospective analysis of 51 patients with achondroplasia and 138 hydrocephalus patients without achondroplasia (48 patients had tumor-related hydrocephalus and 90 patients had hydrocephalus of nontumorous origin) who have visited the authors' institution since 2012 was performed. Preoperative T2-weighted sagittal MR images were used to measure α (steepness of the third ventricle floor), ß (endoscopic angle of incidence), d1 (vertical distance between the dorsum sellae and basilar bifurcation), and d2 (horizontal distance between the dorsum sellae and basilar artery). Each value was compared using the Tukey multicomparison test. RESULTS: Achondroplasia patients showed significantly smaller α (p < 0.001) and ß (p < 0.001) angles, while there were no significant differences between the control groups (p = 0.947 for α, p = 0.836 for ß). The d1 value was significantly larger in achondroplasia patients (p < 0.001), and d2 was smaller (p < 0.001). The control groups showed similar d1 and d2 values (p = 0.415 for d1, p = 0.154 for d2). Smaller α and ß values meant that in achondroplasia patients the third ventricle floor stood more vertically than in other patients with hydrocephalus, and the endoscopic contact angles were small, increasing the risk of ventriculostomy devices slipping down into the infundibular recess. Additionally, a large d1 meant that the basilar artery was shifted upward and a small d2 indicated that the basilar artery was located closer to the dorsum sellae, potentially increasing the risk of basilar artery damage. CONCLUSIONS: Achondroplasia patients' skull and brain anatomies were significantly different from those of other hydrocephalus patients, with steeper third ventricle floors and basilar arteries closer to the dorsum sellae. Because these anatomical differences lead to difficulties in performing ETVs in achondroplasia patients, such differences should be considered when ETV is planned for the patients.

De novo missense variants in HDAC3 leading to epigenetic machinery dysfunction are associated with a variable neurodevelopmental disorder.

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.

Characteristics of chronic enteropathy associated with SLCO2A1 gene (CEAS) in children, a unique type of monogenic very early-onset inflammatory bowel disease.

BACKGROUND:  Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a unique type of inflammatory bowel disease. CEAS is monogenic disease and is thought to develop from childhood, but studies on pediatric CEAS are scarce. We analyzed characteristics of pediatric CEAS. METHODS: Eleven patients diagnosed with CEAS at Seoul National University Children's Hospital were identified and analyzed. Clinical data of patients were collected. Sanger sequencing of SLCO2A1 was performed on all patients. RESULTS: Patients were diagnosed at a median age of 16.0 years (IQR 11.0 ~ 20.0), and the median age at symptoms onset was only 4.0 years (IQR 2.5 ~ 6.0). Growth delay was observed at the time of diagnosis. Patients showed multiple ulcers or strictures in the small intestine, while the esophagus and colon were unaffected in any patients. Almost half of the patients underwent small intestine resection. The major laboratory features of pediatric CEAS include iron deficiency anemia (IDA), hypoalbuminemia, and near-normal levels of C-reactive protein (CRP). Two novel mutations of SLCO2A1 were identified. The most prevalent symptoms were abdominal pain and pale face. None of the immunomodulatory drugs showed a significant effect on CEAS. CONCLUSIONS: Pediatric CEAS typically develop from very young age, suggesting it as one type of monogenic very early onset inflammatory bowel disease. CEAS can cause growth delay in children but there is no effective treatment currently. We recommend screening for SLCO2A1 mutations to pediatric patients with chronic IDA from a young age and small intestine ulcers without elevation of CRP levels.

Congenital central hypoventilation syndrome in korea: 20 years of clinical observation and evaluation of the ventilation strategy in a single center.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children's Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001).   Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known: • Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system. • The disease-defining gene of CCHS is PHOX2B gene - most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 - 20/33). What is New: • We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype. • National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.

Familial chylomicronemia syndrome: case reports of siblings with deletions of the GPIHBP1 gene.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare monogenic form of severe hypertriglyceridemia, caused by mutations in genes involved in triglyceride metabolism. Herein, we report the case of a Korean family with familial chylomicronemia syndrome caused by compound heterozygous deletions of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). CASE PRESENTATION: A 4-year-old boy was referred for the evaluation of severe hypertriglyceridemia (3734 mg/dL) that was incidentally detected 4 months prior. His elder brother also demonstrated an elevated triglyceride level of 2133 mg/dL at the age of 9. Lipoprotein electrophoresis revealed the presence of chylomicrons, an increase in the proportion of pre-beta lipoproteins, and low serum lipoprotein lipase levels. The patient's parents and first elder brother had stable lipid profiles. For suspected FCS, genetic testing was performed using the next-generation sequencing-based analysis of 31 lipid metabolism-associated genes, which revealed no pathogenic variants. However, copy number variant screening using sequencing depth information suggested large heterozygous deletion encompassing all the coding exons of GPIHBP1. A real-time quantitative polymerase chain reaction was performed to validate the deletion site. The results showed that the siblings had two heterozygous copy number variants consisting of the whole gene and an exon 4 deletion, each inherited from their parents. During the follow-up period of 17 months, the patient did not develop pancreatitis, following dietary intervention. CONCLUSION: These siblings' case of familial chylomicronemia syndrome caused by rare GPIHBP1 deletions highlight the implementation of copy number variants-beyond next-generation sequencing-as an important consideration in diagnosis. Accurate genetic diagnosis is necessary to establish the etiology of severe hypertriglyceridemia, which increases the risk of pancreatitis.

Development of disease-specific growth charts for Korean children with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an epigenetic overgrowth syndrome. Despite its distinctive growth pattern, the detailed growth trajectories of children with BWS remain largely unknown. We retrospectively analyzed 413 anthropometric measurements over an average of 4.4 years of follow-up in 51 children with BWS. We constructed sex-specific percentile curves for height, weight, and head circumference using a generalized additive model for location, scale, and shape. Males with BWS exhibited greater height at all ages evaluated, weight before the age of 10, and head circumference before the age of 9 than those of the general population. Females with BWS showed greater height before the age of 7, weight before the age of 4.5, and head circumference before the age of 7 than those of the general population. At the latest follow-up visit at a mean 8.4 years of age, bone age was significantly higher than chronological age. Compared to paternal uniparental disomy (pUPD), males with imprinting center region 2-loss of methylation (IC2-LOM) had higher standard deviation score (SDS) for height and weight, while females with IC2-LOM showed larger SDS for head circumference. These disease-specific growth charts can serve as valuable tools for clinical monitoring of children with BWS.

Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes.

BACKGROUND: Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations. METHODS: Here, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples. RESULTS: In this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%). CONCLUSIONS: Our findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.

The Outcomes of Endoscopic Suturectomy in Syndromic Craniosynostosis.

OBJECTIVE: Endoscopic suturectomy is a widely practiced surgical option for infants with craniosynostosis. But the efficacy and safety of the procedure remain unclear in syndromic patients. This study aims to evaluate the efficacy and safety of endoscopic suturectomy for patients with syndromic craniosynostosis. METHODS: From January 2013 to December 2020, 242 patients underwent endoscopic suturectomy at our institution. The surgical outcome was determined to be favorable or unfavorable based upon the necessity of an additional cranial surgery upon the last follow-up. First, we analyzed the outcomes of 26 syndromic craniosynostosis patients who have followed up for over a year. Second, we compared the outcomes between the syndromic (N=12) and nonsyndromic (N=11) patients with bilateral coronal synostosis who have followed up for over a year. RESULTS: Twenty-three out of 26 syndromic craniosynostosis patients (88%) showed favorable outcomes without significant complications. In the analysis for bilateral coronal synostosis patients, 11 of 12 syndromic patients (92%) presented favorable outcomes, and all nonsyndromic patients showed favorable outcomes. No significant differences were observed in various anthropometric indices (cranial index, intracranial volume, anterior cranial height, anterior cranial base length, and cranial height-length index) and surgical outcomes between syndromic and nonsyndromic groups. CONCLUSIONS: Endoscopic suturectomy has the potential to be a surgical option for syndromic craniosynostosis. Even for patients with unfavorable outcomes, endoscopic suturectomy could serve as a bridge treatment for infants to counter cranial deformation before additional extensive surgery.

Growth patterns of young achondroplasia patients in Korea and predictability of neurosurgical procedures.

BACKGROUND: Achondroplasia is an autosomal dominant disorder mainly affecting bony growth, typically resulting in markedly short stature. From a neurosurgical viewpoint, patients sometimes develop spinal cord compression at the narrowed foramen magnum and hydrocephalus. This study aims to construct growth references for height, weight, and head circumference (HC) of young achondroplasia patients in Korea and to evaluate the predictability of the necessity and timing of neurosurgical procedures through growth patterns. METHODS: Growth data were collected from achondroplasia patients who visited our institution between January 2002 and August 2022. First, we constructed percentile growth curves of height, weight, and HC for the patients under 3 years of age with the generalized additive model for location, scale, and shape (GAMLSS). Second, the growth patterns of the patients with hydrocephalus who underwent neurosurgical procedures such as foramen magnum decompression (FMD) and ventriculoperitoneal (VP) shunt were analyzed. RESULTS: There were 125 achondroplasia patients, including 67 males and 58 females. Among 125 patients, 46 underwent FMD, and 5 underwent VP shunt. As short stature and macrocephaly were typical characteristics of achondroplasia, the height of achondroplasia was lower than that of the general population, and HC in achondroplasia showed accelerated growth postnatally. There were no significant changes in HC in hydrocephalus patients before they underwent neurosurgical procedures. The influence of hydrocephalus on the growth patterns of HC in achondroplasia seemed insignificant. CONCLUSION: Growth references for height, weight, and HC in young achondroplasia patients were constructed. It is the first report of growth patterns of achondroplasia in Korea. Unlike other pediatric patients, the diagnosis of hydrocephalus and the necessity of neurosurgical procedures are hard to be predicted with HC in achondroplasia. Neuroimaging should be considered for achondroplasia patients with neurological symptoms.

A Case Report of Rubinstein-Taybi Syndrome Presenting with Extensive Keloid Formation and Review of Literature.

Rubinstein-Taybi syndrome (RSTS) is an extremely rare genetic disorder affecting multi-organ systems. A tendency to form keloid is one of the common dermatologic manifestations. We describe a 23-year-old female presented with extensive keloids which developed spontaneously. She had typical facial features, broad thumbs, and dental defects, which were suspicious features of genetic syndrome. Direct sequencing for cyclic-AMP-regulated enhancer binding protein revealed a novel mutation. So far, 23 cases of RSTS have been reported in Korean literature. To the best of our knowledge, this is the first report in Korea to describe confirmed case of RSTS with extensive keloids as a chief manifestation.

Recurrent Vascularizing Keratitis in Infants With Hereditary Mucoepithelial Dysplasia Related to SREBF1 Mutation.

PURPOSE: This study aims to present ophthalmic manifestations of 2 infants with hereditary mucoepithelial dysplasia (HMD) related to SREBF1 mutation over a 5-year period. METHODS: Two female infants with an unremarkable perinatal history were evaluated for photophobia that had been manifest since 3 months after birth and diffuse scalp alopecia. Complete ocular examinations under anesthesia were performed, as well as genetic and systemic workup. RESULTS: Both patients had vascularizing keratitis in both eyes, characterized by the growth of corneal new vessels from the 360 degrees periphery to the center and the formation of stromal leucomatous opacity at the leading edge. The keratitis partially regressed in response to topical corticosteroids and waxed and waned during the 5 years of follow-up. In addition, the loss of scalp hair developed in a cyclical pattern, causing diffuse scalp alopecia in the patients. Rheumatologic, nutritional, and developmental evaluations were within normal ranges. Whole-exome sequencing identified a heterozygous c.1669C>T (p.Arg557Cys) pathogenic variant in the SREBF1 gene associated with HMD in both patients. CONCLUSIONS: In pediatric patients with recurrent vascularizing keratitis and diffuse scalp alopecia starting early in life, HMD should be considered, and genetic tests and collaboration with dermatologists and pediatricians on the diagnosis should be provided.

Uncovering the phenotypic consequences of multi-locus imprinting disturbances using genome-wide methylation analysis in genomic imprinting disorders.

Imprinted genes are regulated by DNA methylation of imprinted differentially methylated regions (iDMRs). An increasing number of patients with congenital imprinting disorders (IDs) exhibit aberrant methylation at multiple imprinted loci, multi-locus imprinting disturbance (MLID). We examined MLID and its possible impact on clinical features in patients with IDs. Genome-wide DNA methylation analysis (GWMA) using blood leukocyte DNA was performed on 13 patients with Beckwith-Wiedemann syndrome (BWS), two patients with Silver-Russell syndrome (SRS), and four controls. HumanMethylation850 BeadChip analysis for 77 iDMRs (809 CpG sites) identified three patients with BWS and one patient with SRS showing additional hypomethylation, other than the disease-related iDMRs, suggestive of MLID. Two regions were aberrantly methylated in at least two patients with BWS showing MLID: PPIEL locus (chromosome 1: 39559298 to 39559744), and FAM50B locus (chromosome 6: 3849096 to 3849469). All patients with BWS- and SRS-MLID did not show any other clinical characteristics associated with additional involved iDMRs. Exome analysis in three patients with BWS who exhibited multiple hypomethylation did not identify any causative variant related to MLID. This study indicates that a genome-wide approach can unravel MLID in patients with an apparently isolated ID. Patients with MLID showed only clinical features related to the original IDs. Long-term follow-up studies in larger cohorts are warranted to evaluate any possible phenotypic consequences of other disturbed imprinted loci.

The Korean Genetic Diagnosis Program for Rare Disease Phase II: outcomes of a 6-year national project.

The Korean Genetic Diagnosis Program for Rare Disease (KGDP) enrolled 1890 patients with rare diseases between March 2017 and October 2022. Children and adolescents accounted for the majority of the patients, and systemic disease was the most common presenting symptom. The exome-based virtual disease-specific multigene panel was the most frequently used analytical method, with an overall diagnostic yield of 33.3%. A total of 629 positive cases were diagnosed, involving 297 genes. All 297 genes identified in these cases were confirmed to be known genes listed in the OMIM database. The nationwide KGDP network and its cooperation with the Korean Undiagnosed Diseases Program (KUDP) provide a more comprehensive genetic analysis of undiagnosed cases. The partnership between the KGDP and KUDP has the potential to improve the diagnosis and treatment options for patients. In conclusion, KGDP serves as the primary access point or gateway to KUDP.

Cardiovascular Characteristics and Progressions of Hypertrophic Cardiomyopathy and Pulmonary Stenosis in RASopathy Syndrome in the Genomic Era.

INTRODUCTION: To investigate cardiovascular characteristics and progressions of hypertrophic cardiomyopathy (HCM) and pulmonary stenosis (PS) and determine whether any genotype-phenotype correlations exist in patients with gene-confirmed RASopathy syndrome. STUDY DESIGN: Eighty patients (male, 55%) confirmed as having RASopathy syndrome by genetic testing at a single tertiary center were enrolled. Subjects' medical and echocardiography records were reviewed and the changes in the z scores of left ventricular wall thickness (LVWT) and the degree of PS over time were examined during follow-up of 5.7 ± 3.1 and 7.5 ± 5.2 years, respectively. RESULTS: The most common RASopathy gene identified was PTPN11 (56%), followed by RAF1 (10%). Eighty-five percent of patients had cardiovascular diseases, wherein 42% had HCM, and 38% PS. Mean maximal LVWT z score on the initial echocardiography (mean age 5.0 ± 6.0 years) was 3.4 ± 1.3 (median 2.8, range 2.1-6.6) in the HCM group. Overall, the maximal LVWT increased with time, especially in the HCM group (z = 3.4 ± 1.3 to 3.7 ± 1.6, P = .008) and RAF1-variant group (z = 3.7 ± 1.7 to 4.6 ± 1.8, P = .031). Five patients newly developed HCM during the study period. Genotype-phenotype correlation was significant for HCM (P = .002); 31% of patients with PTPN11 and 88% with RAF1 variants had HCM. PS did not progress in this study cohort. CONCLUSIONS: In this study, progression of ventricular hypertrophy was seen in a significant number of patients with genotype correlation. Thus, long-term follow up of cardiovascular problems in patients with RASopathy is necessary.