The criteria for clinical diagnosis of neurofibromatosis type 1 (NF1) are not sensitive in young children. Recognition is easier when one of their parents has been diagnosed with this condition, and the causal mutation is known. We present a case of a girl with isolated café-au-lait spots, whose father was diagnosed with NF1. However, both were found to carry different de novo mutations in the NF1 gene. This possibility has significant implications for the diagnostic process and genetic counseling.

More than 90% suspected muscular dystrophy (MD) can be confirmed with multiplex ligation-dependent probe amplification (MLPA) combined with targeted panel, although there are a few that cannot be identified. A total of 312 suspected MD patients were enrolled into the study. The MLPA combined with a targeted myopathy panel were performed. Patients with negative results were subjected to whole exome sequencing (WES), whole genome sequencing (WGS), and/or RNA sequencing (RNA-seq). A total of 275 cases were diagnosed as Duchenne/Becker muscular dystrophy (DMD/BMD) and 20 cases were other types of myopathy or nonmuscular diseases. Six female DMD/BMD patients suffered from varying degrees of typical DMD-like symptoms and 2 others were suspected to be gonadal mosaicism. The systematic application of WES, WGS, and/or RNA-seq highlighted the need for the detection of variants missed by the current standard diagnostic procedures. The identification of female patients and mosaic carriers was crucial to predict the risk of recurrence and allow for optimal genetic counseling.

BACKGROUND: An increasing number of clinical trials for new therapeutic strategies are underway or being considered for dystrophinopathy. Having detailed data on the natural progression of this condition is crucial for assessing the effectiveness of new drugs. However, there\'s a lack of data regarding the long-term data on the natural course and how it\'s managed in China. In this study, we offer a comprehensive overview of clinical and molecular findings, as well as treatment outcomes in the Chinese population.
METHODS: Institutional data on all patients with dystrophinopathy from August 2011 to August 2021 were retrospectively reviewed. The data included geographic distribution, age at diagnosis, molecular findings, and treatment options, such as corticosteroids, cardiac interventions, and clinical outcomes.
RESULTS: In total, 2097 patients with dystrophinopathy, including 1703 cases of Duchenne muscular dystrophy (DMD), 311 cases of Becker muscular dystrophy (BMD), 46 cases of intermediate muscular dystrophy (IMD), and 37 cases categorized as \"pending\" (individuals with an undetermined phenotype), were registered in the Children\'s Hospital of Fudan University database for dystrophinopathy from August 2011 to August 2021. The spectrum of identified variants included exonic deletions (66.6%), exonic duplications (10.7%), nonsense variants (10.3%), splice-site variants (4.5%), small deletions (3.5%), small insertions/duplications (1.8%), and missense variants (0.9%). Four deep intronic variants and two inversion variants were identified. Regarding treatment, glucocorticoids were administered to 54.4% of DMD patients and 39.1% of IMD patients. The median age at loss of ambulation was 2.5 years later in DMD patients who received glucocorticoid treatment. Overall, one cardiac medicine at least was prescribed to 7.4% of DMD patients, 8.3% of IMD patients, and 2.6% of BMD patients. Additionally, ventilator support was required by four DMD patients. Eligibility for exon skipping therapy was found in 55.3% of DMD patients, with 12.9%, 10%, and 9.6% of these patients being eligible for skipping exons 51, 53, and 45, respectively.
CONCLUSIONS: This is one of the largest studies to have evaluated the natural history of dystrophinopathy in China, which is particularly conducive to the recruitment of eligible patients for clinical trials and the provision of real-world data to support drug development.

Cystic fibrosis (CF) is an autosomal recessive inherited disease caused by variants of cystic fibrosis transmembrane conductance regulation (CFTR) gene. This report presents a case of a Chinese boy diagnosed with CF, attributed to the presence of two specific CFTR gene variations: 4056G > C (NM_000492.4) (p.Gln1352His, legacy: Q1352H) and c.1210-34TG[13]T[5] (NM_000492.4)(legacy: 5T; TG13). A ten-year-old boy was admitted to the hospital due to recurrent pneumonia, cough, and intermittent fever for seven years. Lung auscultation revealed rales, and a lung CT scan indicated parenchymal transformation with infection in both lungs. Whole Exome Sequencing (WES) identified two CFTR gene variants, Q1352H and 5T; TG13, which were significantly associated with clinical phenotype. Following a two-year course of azithromycin combined with inhalation therapy with budesonide, the patient experienced no further episodes of respiratory infections. Moreover, significant improvements were observed in pulmonary function, pulmonary infection, and bronchiectasis. The occurrence of combined variations, Q1352H and 5T; TG13, in the CFTR gene is rare and specific to Chinese populations. WES proves to be a valuable diagnostic tool for detecting CFTR gene variants.

Ovarian cancer is a malignant tumor that seriously endangers health. Early ovarian cancer symptoms are frequently challenging to detect, resulting in a large proportion of patients reaching an advanced stage when diagnosed. Conventional diagnosis relies heavily on serum biomarkers and pathological examination, but their sensitivity and specificity require improvement. Targeted therapy inhibits tumor growth by targeting certain characteristics of tumor cells, such as signaling pathways and gene mutations. However, the effectiveness of targeted therapy varies among individuals due to differences in their unique biological characteristics and requires individualized strategies. Immunotherapy is a promising treatment for ovarian cancer due to its long-lasting antitumor effect. Nevertheless, issues such as variable efficacy, immune-associated adverse effects and drug resistance remain to be resolved. The present review discusses the diagnostic strategies, rationale, treatment strategies and prospects of targeted therapy and immunotherapy for ovarian cancer.

Accurate interpretation of sequence variants in inherited retinal dystrophy (IRD) is vital given the significant genetic heterogeneity observed in this disorder. To achieve consistent and accurate diagnoses, establishment of standardized guidelines for variant interpretation is essential. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation serve as the global \"cross-disease\" standard for classifying variants in Mendelian hereditary disorders. These guidelines propose a systematic approach for categorizing variants into 5 classes based on various types of evidence, such as population data, computational data, functional data, and segregation data. However, for clinical genetic diagnosis and to ensure standardized diagnosis and treatment criteria, additional specifications based on features associated with each disorder are necessary. In this context, we present a comprehensive framework outlining the newly specified ACMG/AMP rules tailored explicitly to IRD in the Japanese population on behalf of the Research Group on Rare and Intractable Diseases (Ministry of Health, Labour and Welfare of Japan). These guidelines consider disease frequencies, allele frequencies, and both the phenotypic and the genotypic characteristics unique to IRD in the Japanese population. Adjustments and modifications have been incorporated to reflect the specific requirements of the population. By incorporating these IRD-specific factors and refining the existing ACMG/AMP guidelines, we aim to enhance the accuracy and consistency of variant interpretation in IRD cases, particularly in the Japanese population. These guidelines serve as a valuable resource for ophthalmologists and clinical geneticists involved in the diagnosis and treatment of IRD, providing them with a standardized framework to assess and classify genetic variants.

Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient\'s muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.

More than 450 genetic defects result in inborn errors of immunity (IEI). Their individual prevalence in specific cohorts is influenced by national characteristics and other factors. We present results of genetic testing conducted in 1809 Russian children with IEI. Genetic defects confirming IEI were found in 1112 out of 1809 (61.5%) probands. These defects included variants in 118 single genes (87.9% of patients) and aberrations in 6 chromosomes (11.8%). Notably, three patients harbored pathogenic variants in more than one IEI gene. Large deletions constituted 5% of all defects. Out of the 799 original variants, 350 (44%) have not been described previously. Rare genetic defects (10 or fewer patients per gene) were identified in 20% of the patients. Among 967 probands with germline variants, defects were inherited in an autosomal dominant manner in 29%, X-linked in 34%, and autosomal recessive in 37%. Four females with non-random X-inactivation exhibited symptoms of X-linked diseases (BTK, WAS, CYBB, IKBKG gene defects). Despite a relatively low rate of consanguinity in Russia, 47.9% of autosomal recessive gene defects were found in a homozygous state. Notably, 28% of these cases carried \"Slavic\" mutation of the NBN gene or known hot-spot mutations in other genes. The diversity of IEI genetic forms and the high frequency of newly described variants underscore the genetic heterogeneity within the Russian IEI group. The new variants identified in this extensive cohort will enrich genetic databases.

Osteopetrosis is a clinically and genetically heterogeneous group of inherited bone disorders that is caused by defects in osteoclast formation or function. Treatment options vary with the disease severity and an accurate molecular diagnosis helps in prognostication and treatment decisions. We investigated the genetic causes of osteopetrosis in 31 unrelated patients of Indian origin. Screening for the genetic variants was done by Sanger sequencing or next generation sequencing in 48 samples that included 31 samples from index patients, 16 from parents\' and 1 chorionic villus sample. A total of 30 variants, including 29 unique variants, were identified in 26 of the 31 patients in the study. TCIRG1 was the most involved gene (n = 14) followed by TNFRSF11A (n = 4) and CLCN7 (n = 3). A total of 17 novel variants were identified. Prenatal diagnosis was done in one family and the foetus showed homozygous c.807 + 2T > G variant in TCIRG1. Molecular diagnosis of osteopetrosis aids in therapeutic decisions including the need for a stem cell transplantation and gives a possible option of performing prenatal diagnosis in affected families. Further studies would help in understanding the genetic etiology in patients where no variants were identified.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12288-023-01732-4.

BACKGROUND: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end.
METHODS: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes.
RESULTS: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets.
CONCLUSIONS: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.