Gene therapy has made considerable strides in recent years. More than 4000 protein-coding genes have been implicated in more than 6000 genetic diseases; next-generation sequencing has dramatically revolutionized the diagnosis of genetic diseases. Most genetic diseases are considered very rare or ultrarare, defined here as having fewer than 1:100,000 cases, but only one of the 12 approved gene therapies (excluding RNA therapies) targets an ultrarare disease. This article explores three gene supplementation therapy approaches suitable for various rare genetic diseases: lentiviral vector-modified autologous CD34+ hematopoietic stem cell transplantation, systemic delivery of adeno-associated virus (AAV) vectors to the liver, and local AAV delivery to the cerebrospinal fluid and brain. Together with RNA therapies, we propose a potential business model for these gene therapies.

Inborn errors of immunity (IEI) are a diverse and growing category of more than 430 chronic disorders that share susceptibilities to infections. Whether the result of a genetic lesion that causes defective granule-dependent cytotoxicity, excessive lymphoproliferation, or an overwhelming infection represents a unique antigenic challenge, IEIs can display a proclivity for cytokine storm syndrome (CSS) development. This chapter provides an overview of CSS pathophysiology as it relates to IEIs. For each IEI, the immunologic defect and how it promotes or discourages CSS phenomena are reviewed. The IEI-associated molecular defects in pathways that are postulated to be critical to CSS physiology (i.e., toll-like receptors, T regulatory cells, the IL-12/IFNγ axis, IL-6) and, whenever possible, review strategies for treating CSS in IEI patients with molecularly directed therapies are highlighted.

Various rare inherited disorders can be associated with kidney involvement, including glomerulopathies, tubulopathies, multiple cysts, congenital anomalies of the kidneys and urinary tract, urolithiasis, malignant and benign tumors. Genetic nephropathy should be always considered in children, adolescents and young patients with the kidneys or urinary tract disorders and/or patients with positive family anamnesis. Extrarenal manifestations can be a valuable clue for diagnosis of certain hereditary diseases, e.g. neurosensory deafness in Alport syndrome or photofobia in nephropathic cystinosis. Diagnosis of monogenic inherited diseases should be verified by genetic testing. Specific drugs are available for treatment of certain hereditary diseases involving kidney, e.g. Fabry disease, cystinosis, primary hyperoxaluria I type and atypical hemolytic uremic syndrome.
При редких наследственных заболеваниях могут наблюдаться гломерулопатии, тубулопатии, поликистоз, аномалии почек и мочевыводящих путей, уролитиаз, злокачественные или доброкачественные опухоли. Наследственные нефропатии в первую очередь следует предполагать при появлении признаков поражения почек в детском, подростковом или молодом возрасте и/или при наличии семейного анамнеза. При системных заболеваниях важное диагностическое значение имеют внепочечные проявления (например, нейросенсорная тугоухость при синдроме Альпорта или отложение кристаллов цистина в роговице при нефропатическом цистинозе). Для подтверждения диагноза моногенного наследственного заболевания проводят молекулярно-генетическое исследование. При некоторых орфанных заболеваниях, поражающих почки, таких как болезнь Фабри, цистиноз, первичная гипероксалурия 1-го типа и атипичный гемолитико-уремический синдром, возможна специфическая патогенетическая терапия.

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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.

Objective: To explore the genetic etiology of pediatric intensive care unit (PICU) mortality cases and summarize their clinical characteristics. Methods: This was a retrospective cohort study. The study population consisted of 234 children who died within 7 d after admitted to the PICU of Children\'s Hospital of Fudan University from January 2017 to December 2021. The clinical diagnoses, laboratory test results, and genetic testing results were collected. These patients were divided into the pathogenic gene variation positive (PGVP) group and the pathogenic gene variation negative (PGVN) group according to the results of genetic testing. The Mann-Whitney U test and Pearson\'s chi-square test or Fisher\'s exact probability method were used to compare the clinical characteristics between the groups. Results: A total of 234 cases were enrolled, including 139 (59.4%) males and 95 (40.6%) females. The age at death was 1.0 (0.4, 3.7) years old and the length of PICU stay was 16 (6, 33) days. There were 62 cases (26.5%) PGVP, and the mutated pathogenic genes included immune genes (23 cases (37.1%)), metabolic genes (11 cases (17.7%)), neuromuscular genes (11 cases (17.7%)), cardiovascular genes (4 cases (6.5%)), and genes of other systems (13 cases (21.0%)). The age at death in PGVP cases was significantly lower than in PGVN cases (0.6 (0.3, 1.4) vs. 1.3(0.5, 4.3) years old, Z=3.85, P<0.001). Compared with the PGVN group, the PGVP group had a higher incidence of family history and chronic complex conditions (CCC) than the PGVN group (6.5% (4/62) vs. 0.6% (1/172) and 93.5% (58/62) vs. 76.2% (131/172), χ2=8.87, P=0.018 and 0.003, respectively). Children in the PGVP group were admitted with higher incidence of severe infection, decreased consciousness or coma, moderate-to-severe anemia, thrombocytopenia, protracted diarrhea, and abnormalities in muscle strength or tone than those in the PGVN group (74.2%(46/62) vs. 45.9%(79/172), 50.0%(31/62) vs. 35.5%(61/172), 32.3%(20/62) vs. 18.0%(31/172), 21.0%(13/62) vs. 10.5%(18/172), 25.8%(16/62) vs. 4.1%(7/172), 16.1%(10/62) vs. 5.2%(9/172), χ2=14.63, 4.04, 5.41, 4.37, 24.30, 7.25, all P<0.05). Pathogenic genes that occurred more than twice included IL2RG (5 cases), SMN1 (4 cases), and SH2D1A (3 cases, including 2 single gene varients and 1 copy number varient). Conclusions: Among the deceased cases in the PICU, the main genetic causes are immune-related, metabolic, and neuromuscular genetic disorders. Critically ill children with a family history, CCC, and early features such as severe infections, decreased consciousness or coma, moderate to severe anemia, thrombocytopenia, protracted diarrhea, or abnormalities in muscle strength or tone should be closely monitored and undergo early genetic testing.
目的： 探索儿童重症监护病房（PICU）死亡病例的遗传病因并总结其临床特征。 方法： 回顾性队列研究。选择2017年1月至2021年12月复旦大学附属儿科医院PICU怀疑遗传病入院后7 d内死亡的234例患儿为研究对象，收集临床诊断、实验室检查等临床信息和基因检测结果，根据基因检测结果分为致病性基因变异阳性（PGVP）组和致病性基因变异阴性（PGVN）组，采用Mann-Whitney U检验和Pearson χ²检验或Fisher确切概率法比较组间的临床特征差异。 结果： 234例死亡病例中男139例（59.4%）、女95例（40.6%），死亡年龄为1.0（0.4，3.7）岁，住院时长为16（6，33）d。其中PGVP组62例（26.5%），变异的致病性基因包括免疫基因［23例（37.1%）］、代谢基因［11例（17.7%）］、神经肌肉基因［11例（17.7%）］、心血管基因［4例（6.5%）］和其他系统基因［13例（21.0%）］。PGVP组的死亡年龄低于PGVN组［0.6（0.3，1.4）比1.3（0.5，4.3）岁，Z=3.85，P<0.001］；存在家族史和慢性复杂疾病（CCC）的情况均多于PGVN组［6.5%（4/62）比0.6%（1/172）、93.5%（58/62）比76.2%（131/172），χ2=8.87，P=0.018、0.003］。PGVP组患儿入院存在重症感染、精神反应差或昏迷、中重度贫血、血小板减少、迁延性腹泻、肌力或肌张力异常的比例均高于PGVN组［74.2%（46/62）比45.9%（79/172）、50.0%（31/62）比35.5%（61/172）、32.3%（20/62）比18.0%（31/172）、21.0%（13/62）比10.5%（18/172）、25.8%（16/62）比4.1%（7/172）、16.1%（10/62）比5.2%（9/172），χ2=14.63、4.04、5.41、4.37、24.30、7.25，均P<0.05］。出现2次以上的致病基因包括IL2RG（5例）、SMN1（4例）、SH2D1A（3例，包括2例单基因变异和1例拷贝数变异）。 结论： PICU死亡病例的遗传基因主要为免疫、代谢和神经肌肉遗传病基因。对存在家族史、CCC和入院时存在重症感染、精神反应差或昏迷、中重度贫血、血小板减少、迁延性腹泻、肌力或肌张力异常等特征的患儿应重点关注并尽早行基因检测。.

BACKGROUND: Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent-offspring trios and proband only analysis.
METHODS: We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation.
RESULTS: Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications.
CONCLUSIONS: CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.

OBJECTIVE: Analysis of the F8 gene helps predict the risk of developing factor VIII (FVIII) inhibitors and the depth of phenotype in haemophilia A (HA) patients. Since data in Southeast Asian countries remain scarce, we aim to study F8 variation correlated with HA phenotypes in Thailand.
METHODS: Thai patients with HA were enrolled from seven haemophilia treatment centres during 2022-2023. Using peripheral blood DNA, inverse shifting-polymerase chain reaction (IS-PCR) for F8-intron 22 inversion (Inv22) and F8-intron 1 inversion (Inv1) was performed. Whole exome sequencing (WES) was explored in cases without Inv22/Inv1.
RESULTS: Of 124 patients with HA, 91.9% were detected with a causative F8 variant, including Inv22 (30.6%), Inv1 (1.6%), missense (23.4%), nonsense (16.9%) and small insertion/deletion (16.1%) mutations. Inv22, small insertion/deletion and nonsense were associated with severe HA, compared with missense variants, by the ORs of 13.9 (95% CI, 4.2 to 56.7), 14.7 (95% CI, 3.4 to 104.7) and 15.6 (95% CI, 3.6 to 110.2), respectively. While nonsense variants affecting the light chain increased the risk of developing FVIII inhibitors (OR, 6.8; 95% CI, 1.5 to 32.6) compared with the low-risk (small insertion/deletion, missense and splice-site) variants. Twelve patients (9.7%) harboured novel F8 variants, comprising five missense (p.Pro540Leu, p.Ser564Pro, p.Leu668Pro, p.Ala1721Glu, p.His2024Pro), five small insertion/deletion (p.Val502SerfsTer13, p.Ile522PhefsTer13, p.Phe992LysfsTer11, p.Leu1223PhefsTer18, c.6427_6429+3delATGGTA) and one nonsense mutations (p.Glu1292Ter).
CONCLUSIONS: IS-PCR followed by WES successfully assesses F8 alterations in most HA cases. With several unique variants, severe HA in Thailand is considerably caused by Inv22, small insertion/deletion and nonsense, whereas missense variants are more responsible for nonsevere HA phenotypes.

BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.
METHODS: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.
RESULTS: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.
CONCLUSIONS: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.