Infantile nystagmus syndrome (INS) refers to congenital forms of nystagmus that are present at birth or during infancy. This syndrome may be caused by afferent visual system disorders or abnormal development of the ocular motor system. INS is a genetically heterogeneous disorder for which there are more than 100 causative genes. Since applying clinical tests for the differential diagnosis of INS can be challenging in early infancy and children, genetic testings such as next-generation sequencing are becoming more important for achieving accurate diagnoses. An improved understanding of the molecular mechanisms of INS may also lead to the development of gene-based therapies for INS. These advantages of genetic testing have the potential to change the diagnostic paradigm of patients with INS. However, the diagnostic pathway based on genetic testing still has several limitations in terms of the therapeutic effect and methodology. This review summarizes genetic and clinical features of INS, and discusses the promise and pitfalls of genetic testing in INS.

Despite advances in the diagnosis and management of rare diseases (RDs), there remains a tendency to overlook adult RD patients. In addition to the considerable number of adult-onset RDs, advances in the diagnosis and management of pediatric RDs have led to an increase in the survival of these patients into adulthood. Adult RDs exhibit distinct features from pediatric counterparts, necessitating careful consideration during medical assessments. Given the extended life expectancy of adult RD patients, precise diagnosis and management strategies can significantly enhance patient outcomes. This review aims to provide an in-depth exploration of the characteristics unique to adult RDs. Special emphasis will be placed on the importance of cascade screening and prenatal genetic testing in the context of adult RDs, highlighting the need for a comprehensive understanding of these aspects in clinical practice.

Purpose: Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant diseases caused by heterozygous mutation in the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of a high number of partial pseudogenes, and the great variety of mutations. We aimed to study the mutation spectrum of NF1 gene in Korean patients with NF1. Materials and Methods: We have analyzed total 69 unrelated patients who were clinically diagnosed with NF1. PCR and sequencing of the NF1 gene was performed in all unrelated index patients. Additionally, multiplex ligation-dependent probe amplification (MLPA) test of the NF1 and SPRED1 gene analysis (sequencing and MLPA test) were performed in patients with negative results from NF1 gene sequencing analysis. Results: Fifty-five different variants were identified in 60 individuals, including six novel variants. The mutations included 36 single base substitutions (15 missense and 21 nonsense), eight splicing mutations, 13 small insertion or deletions, and three gross deletions. Most pathogenic variants were unique. The mutations were evenly distributed across exon one through 58 of NF1, and no mutational hot spots were found. When fulfilling the National Institutes of Health criterion for the clinical diagnosis of NF1, the detection rate was 84.1%. Cafe-au-lait macules were observed in all patients with NF1 mutations. There is no clear relationship between specific mutations and clinical features. Conclusion This study revealed a wide spectrum and genetic basis of patients with NF1 in Korea. Our results aim to contribute genetic management and counseling.

Rare diseases are characterized by a low prevalence, which often means that patients with such diseases are undiagnosed and do not have effective treatment options. Neurodevelopmental and neurological disorders make up around 40% of rare diseases and in the past decade, there has been a surge in the identification of genes linked to these conditions. This has created the need for model organisms to reveal mechanisms and to assess therapeutic methods. Different model animals have been employed, like Caenorhabditis elegans, Drosophila, zebrafish, and mice, to investigate the rare neurological diseases and to identify the causative genes. While the zebrafish has become a popular animal model in the last decade, mainly for studying brain development, understanding neural circuits, and conducting chemical screens, the mouse has been a very well-known model for decades. This review explores the strengths and limitations of using zebrafish as a vertebrate animal model for rare neurological disorders, emphasizing the features that make this animal model promising for the research on these disorders.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome is a maternally inherited mitochondrial disorder that usually affects the cerebral cortex and prevents high-energy demands from being met. Herein, we present the case of a male patient who rapidly developed multiple seizures, headaches, and altered mentality accompanied by severe metabolic acidosis and lactic acidosis. Initially, a brain imaging study confirmed stroke-like lesions (SLLs) only in the cerebellum. During follow-up, newly developed SLLs with lactic acidosis were observed in the basal ganglia (BG), cerebellum, and occipital lobe. The m.3243A>G variant had been found in the patient and MELAS was diagnosed, despite the BG and cerebellum being atypical locations for SLLs in MELAS. Since most cases of m.3243A>G variant MELAS show SLLs in the cerebral cortex, this case is unusual considering the location of the lesion. We emphasize that in the case of lactic acidosis accompanied by neurological symptoms, such as seizures, as in this case, MELAS should be included in the differential diagnosis, even if SLLs are observed in areas other than the cerebral cortex.

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked neurodevelopmental disorder with abnormal thyroid function caused by mutation in the solute carrier family 16 member 2 (SLC16A2) gene. Clinical manifestations of AHDS are global or axial hypotonia, a variety of movement disorders, severe intellectual disability, quadriplegia or spastic diplegia, growth failure, and seizures. A 10-year-old boy visited our hospital with the chief complaint of newly onset generalized tonic seizures with vocalization of weekly to daily frequency. He showed early infantile hypotonia, severe intellectual disability, and frequent respiratory infections. He could not walk independently and was non-verbal. Electroencephalogram revealed generalized slow spike and waves with multifocal spikes and slow background rhythms. His tonic seizures were controlled with more than two anti-seizure medications (ASMs). At 11 years of age, he was evaluated for thyroid function as part of regular screening for ASM maintenance and was found to have abnormal thyroid function. We performed whole exome sequencing for severe global developmental delay, drug-resistant epilepsy, and abnormal thyroid function. The hemizygous c.940C>T (p.Arg314Ter) variant in the SLC16A2 gene (NM_006517.5) was identified and confirmed based on Sanger sequencing. Herein, we describe a case of an AHDS patient with late-onset drug-resistant epilepsy combined with congenital hypotonia, global developmental delay, and abnormal thyroid function results. To the best of our knowledge, this is the oldest adolescent among AHDS cases reported in Korea. In this report, clinical characteristics of a mid-adolescence patient with AHDS were presented.

As advanced sequencing technologies continue to uncover an increasing number of variants in genes associated with human genetic diseases, there is a growing demand for systematic approaches to assess the impact of these variants on human development, health, and disease. While in silico analyses have provided valuable insights, it is essential to complement these findings with model organism studies to determine the functional consequences of genetic variants in vivo. Drosophila melanogaster is an excellent genetic model for such functional studies due to its efficient genetic technologies, high gene conservation with humans, accessibility to mutant fly resources, short life cycles, and cost-effectiveness. The traditional GAL4-UAS system, allowing precise control of gene expression through binary regulation, is frequently employed to assess the effects of monoallelic variants. Recombinase medicated cassette exchange or CRISPR-Cas9-mediated GAL4 insertion within coding introns or substitution of gene body with Kozak-Gal4 result in the loss-of-function of the target gene. This GAL4 insertion strategy also enables the expression of reference complementary DNA (cDNA) or cDNA carrying genetic variants under the control of endogenous regulatory cis elements. Furthermore, the CRISPR-Cas9-directed tissue-specific knockout and cDNA rescue system provides the flexibility to investigate candidate variants in a tissue-specific and/or developmental-timing dependent manner. In this review, we will delve into the diverse genetic techniques available in Drosophila and their applications in diagnosing and studying numerous undiagnosed diseases over the past decade.

Rare diseases, even though defined as fewer than 20,000 in South Korea, with over 8,000 rare Mendelian disorders having been identified, they collectively impact 6-8% of the global population. Many of the rare diseases pose significant challenges to patients, patients’ families, and the healthcare system. The diagnostic journey for rare disease patients is often lengthy and arduous, hampered by the genetic diversity and phenotypic complexity of these conditions. With the advent of nextgeneration sequencing technology and clinical implementation of exome sequencing (ES) and genome sequencing (GS), the diagnostic rate for rare diseases is 25-50% depending on the disease category. It is also allowing more rapid new gene-disease association discovery and equipping us to practice precision medicine by offering tailored medical management plans, early intervention, family planning options. However, a substantial number of patients remain undiagnosed, and it could be due to several factors. Some may not have genetic disorders. Some may have disease-causing variants that are not detectable or interpretable by ES and GS. It's also possible that some patient might have a disease-causing variant in a gene that hasn't yet been linked to a disease. For patients who remain undiagnosed, reanalysis of existing data has shown promises in providing new molecular diagnoses achieved by new gene-disease associations, new variant discovery, and variant reclassification, leading to a 5-10% increase in the diagnostic rate. More advanced approach such as long-read sequencing, transcriptome sequencing and integration of multi-omics data may provide potential values in uncovering elusive genetic causes.

Exonic copy number variation (CNV), involving deletions and duplications at the gene’s exon level, presents challenges in detection due to their variable impact on gene function. The study delves into the complexities of identifying large CNVs and investigates less familiar but recurrent exonic CNVs, notably enriched in East Asian populations. Examining specific cases like DRC1, STX16, LAMA2, and CFTR highlights the clinical implications and prevalence of exonic CNVs in diverse populations.The review addresses diagnostic challenges, particularly for single exon alterations, advocating for a strategic, multi-method approach. Diagnostic methods, including multiplex ligation-dependent probe amplification, droplet digital PCR, and CNV screening using next-generation sequencing data, are discussed, with whole genome sequencing emerging as a powerful tool. The study underscores the crucial role of ethnic considerations in understanding specific CNV prevalence and ongoing efforts to unravel subtle variations. The ultimate goal is to advance rare disease diagnosis and treatment through ethnicallyspecific therapeutic interventions.

CCCTC-binding factor (CTCF) is a transcriptional regulator that binds to a complex DNA motif in various orientations and plays a crucial role in regulating gene expression, chromatin restructuring, and developmental processes. Mutations in the CTCF are associated with neurodevelopmental disorders. Here we report the first Korean case with a de novo heterozygous variant in the CTCF (c.1025G>A; p.Arg342His). She showed global developmental delay, failure to thrive, and dysmorphic face, which are phenotypes consistent with previous reports in the autosomal dominant intellectual developmental disorder 21 (MIM 615502). She also showed clinical features not previously reported, such as antral web and tracheobronchomalacia.Our case follows suit and expands understanding of this rare disorder by reporting common features and, on the other hand, unreported concomitant congenital anomalies.