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Fowzan Alkuraya and colleagues report the identification of a truncating mutation in DNASE1L3 in six families with an autosomal recessive Mendelian form of systemic lupus erythematosus, a complex autoimmune disease. Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3 -related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease–gene links following previous reports ( TRAK1 , GTF3C3 , SPTBN4 and NKX6 - 2 ), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates ( ANKHD1 , ASTN2 , ATP13A1 , FMO4 , MADD , MFSD11 , NCKAP1 , NFASC , PCDHGA10 , PPP1R21 , SLC12A2 , SLK , STK32C and ZFAT ). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

ABSTRACT Neonatal diabetes mellitus (NDM) is a monogenic condition diagnosed <6 months of age with >40 genetic causes. International guidelines recommend referral for genetic testing immediately after diagnosis since the genetic result guides clinical management. We used next‐generation sequencing to identify a homozygous pathogenic variant, p.(Arg244*), in COQ9 in 2 individuals referred for NDM testing. Both had insulin‐treated hyperglycemia, severe structural brain defects, dysmorphic features, and lactic acidosis. Recessive loss‐of‐function variants in COQ9 cause Coenzyme Q10 deficiency‐5, a multi‐system mitochondrial disease, with 7 cases reported. Neonatal hyperglycemia has not been reported in any of these cases but has been described for two other Coenzyme Q10 disorders caused by variants in COQ2 and COQ4. Our report shows that individuals with COQ9‐related disease can present with neonatal hyperglycemia, expanding the clinical spectrum of this disorder. We recommend the inclusion of COQ9, as well as COQ2 and COQ4, to gene panels used for NDM testing. NDM is a monogenic condition diagnosed <6 months. We present the first two cases of individuals with pathogenic variants in COQ9 who presented with neonatal hyperglycemia. COQ9 should be included on NDM genetic testing panels.

Background Osteogenesis imperfecta (OI) is an hereditary bone disease in which increased bone fragility leads to frequent fractures and other complications, usually in an autosomal dominant fashion. An expanding list of genes that encode proteins related to collagen metabolism are now recognised as important causes of autosomal recessive (AR) OI. Our aim was to study the contribution of known genes to AR OI in order to identify novel loci in mutation-negative cases. Methods We enrolled multiplex consanguineous families and simplex cases (also consanguineous) in which mutations in COL1A1 and COL1A2 had been excluded. We used autozygome guided mutation analysis of AR OI (AR OI) genes followed by exome sequencing when such analysis failed to identify the causative mutation. Results Two simplex and 11 multiplex families were enrolled, encompassing 27 cases. In three multiplex families, autozygosity and linkage analysis revealed a novel recessive OI locus on chromosome 9q31.1-31.3, and a novel truncating deletion of exon 4 of TMEM38B was identified within that interval. In addition, gonadal or gonadal/somatic mosaic mutations in COL1A1 or COL1A2 and homozygous mutations in recently described AR OI genes were identified in all remaining families. Conclusions TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.

To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. Detailed phenotyping and next-generation sequencing (panel and exome). Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello–Carey syndrome–like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Variant nomenclature discrepancy was identified in the article.

Artificial Intelligent (AI) applications in e-health have evolved considerably in the last 25 years. To track the current research progress in this field, there is a need to analyze the most recent trend of adopting AI applications in e-health. This bibliometric analysis study covers AI applications in e-health. It differs from the existing literature review as the journal articles are obtained from the Scopus database from its beginning to late 2021 (25 years), which depicts the most recent trend of AI in e-health. The bibliometric analysis is employed to find the statistical and quantitative analysis of available literature of a specific field of study for a particular period. An extensive global literature review is performed to identify the significant research area, authors, or their relationship through published articles. It also provides the researchers with an overview of the work evolution of specific research fields. The study's main contribution highlights the essential authors, journals, institutes, keywords, and states in developing the AI field in e-health.