Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

Calame, Daniel G.; Guo, Tianyu; Wang, Chen; Garrett, Lillian; Jolly, Angad; Dawood, Moez; Kurolap, Alina; Henig, Noa Zunz; Fatih, Jawid M.; Herman, Isabella; Du, Haowei; Mitani, Tadahiro; Becker, Lore; Rathkolb, Birgit; Gerlini, Raffaele; Seisenberger, Claudia; Marschall, Susan; Hunter, Jill V.; Gerard, Amanda; Heidlebaugh, Alexis; Challman, Thomas; Spillmann, Rebecca C.; Jhangiani, Shalini N.; Coban-Akdemir, Zeynep; Lalani, Seema; Liu, Lingxiao; Revah-Politi, Anya; Iglesias, Alejandro; Guzman, Edwin; Baugh, Evan; Boddaert, Nathalie; Rondeau, Sophie; Ormieres, Clothide; Barcia, Giulia; Tan, Queenie K.G.; Thiffault, Isabelle; Pastinen, Tomi; Sheikh, Kazim; Biliciler, Suur; Mei, Davide; Melani, Federico; Shashi, Vandana; Yaron, Yuval; Steele, Mary; Wakeling, Emma; Østergaard, Elsebet; Nazaryan-Petersen, Lusine; Millan, Francisca; Santiago-Sim, Teresa; Thevenon, Julien; Bruel, Ange-Line; Thauvin-Robinet, Christel; Popp, Denny; Platzer, Konrad; Gawlinski, Pawel; Wiszniewski, Wojciech; Marafi, Dana; Pehlivan, Davut; Posey, Jennifer E.; Gibbs, Richard A.; Gailus-Durner, Valerie; Guerrini, Renzo; Fuchs, Helmut; Hrabě de Angelis, Martin; Hölter, Sabine M.; Cheung, Hoi-Hung; Gu, Shen; Lupski, James R.

doi:10.1016/j.ajhg.2023.06.013

Cited by 16 publications

(6 citation statements)

References 70 publications

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“…Isolated DNA was analyzed for purity and molecular weight using PicoGreen and gel imaging. After DNA quality control tests, Illumina sequencing libraries with incorporated barcodes were produced following standard procedures (48) using human genome sequencing center custom exome design (HG38_HGSC_Twist_Comprehensive_Exome) and Rhesus Spike-In probes following manufacturer’s protocol (https://www.twistbioscience.com/). This new design is a modification of our previous Rhexome design using NimbleGen Human whole exome probes plus rhesus-specific probes (49).…”

Section: Methodsmentioning

confidence: 99%

Complete genomic assembly of Mauritian cynomolgus macaque killer immunoglobulin-like receptor and natural killer group 2 haplotypes

Prall,

Karl,

Varghese

et al. 2023

Preprint

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Mauritian-origin cynomolgus macaques (MCM) serve as a powerful nonhuman primate model in biomedical research due to their unique genetic homogeneity, which simplifies experimental designs. Despite their extensive use, a comprehensive understanding of crucial immune-regulating gene families, particularly killer immunoglobulin-like receptors (KIR) and natural killer group 2 (NKG2), has been hindered by the lack of detailed genomic reference assemblies. In this study, we employ advanced long-read sequencing techniques to completely assemble eight KIR and seven NKG2 genomic haplotypes, providing an extensive insight into the structural and allelic diversity of these immunoregulatory gene clusters. Leveraging these genomic resources, we prototype a strategy for genotyping KIR and NKG2 using short-read, whole exome capture data, illustrating the potential for cost-effective multi-locus genotyping at colony scale. These results mark a significant enhancement for biomedical research in MCMs and underscores the feasibility of broad-scale genetic investigations.

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Section: Methodsmentioning

confidence: 99%

Complete genomic assembly of Mauritian cynomolgus macaque killer immunoglobulin-like receptor and natural killer group 2 haplotypes

Prall,

Karl,

Varghese

et al. 2023

Preprint

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“…In contrast, the study of rare genetic variation has only just begun. An explosion of neurodevelopmental disease-gene associations has resulted from family-based studies, next generation sequencing, and online gene matchmaking [ 4 , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ], but genome-wide functional annotation requires greater international integration of human genomic and phenotypic data. National programs like UK Biobank and All of Us represent an important step in this direction [ 129 , 130 ], but a wealth of genomic and phenotypic data remains locked away in data silos: research databases, clinical diagnostic laboratories, and electronic health records.…”

Section: Functional Genomics Of Mitochondrial Neurodevelopmental Diso...mentioning

confidence: 99%

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Calame,

Emrick

2024

Neurotherapeutics

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“…To comprehensively characterize the phenotypic spectrum of FLVCR1 -related disorders in humans, we reanalyzed ES and genome sequencing (GS) data from the 29,766 individuals within the BCM-GREGoR and Baylor Genetics clinical diagnostic databases 22 , utilized the online matchmaking program GeneMatcher 23,24 , and searched other research and diagnostic lab datasets. We identified 27 individuals from 20 unrelated families with neurological disorders and biallelic FLVCR1 variants ( Fig.…”

Section: Textmentioning

confidence: 99%

Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

Calame,

Wong,

Panda

et al. 2024

Preprint

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FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

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Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

Cited by 16 publications

References 70 publications

Complete genomic assembly of Mauritian cynomolgus macaque killer immunoglobulin-like receptor and natural killer group 2 haplotypes

Complete genomic assembly of Mauritian cynomolgus macaque killer immunoglobulin-like receptor and natural killer group 2 haplotypes

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

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