<i>EXTL3</i> mutations cause skeletal dysplasia, immune deficiency, and developmental delay

Volpi, Stefano; Yamazaki, Yasuhiro; Brauer, Patrick M.; Rooijen, Ellen van; Hayashida, Atsuko; Slavotinek, Anne; Kuehn, Hye Sun; Rocco, Maja Di; Rivolta, Carlo; Bortolomai, Ileana; Du, Likun; Felgentreff, Kerstin; Bruin, Lisa Ott de; Hayashida, Kazutaka; Freedman, George; Marcovecchio, Genni Enza; Capuder, Kelly; Rath, Pramod C.; Luche, Nicole; Hagedorn, Elliott J.; Buoncompagni, Antonella; Royer‐Bertrand, Béryl; Giliani, Silvia; Poliani, Pietro Luigi; Imberti, Luisa; Dobbs, Kerry; Poulain, Fabienne E.; Martini, Alberto; Manis, John P.; Linhardt, Robert J.; Bosticardo, Marita; Rosenzweig, Sergio D.; Lee, Hane; Puck, Jennifer M.; Zúñiga‐Pflücker, Juan Carlos; Zon, Leonard I.; Park, Pyong Woo; Superti‐Furga, Andrea; Notarangelo, Luigi D.

doi:10.1084/jem.20161525

Cited by 72 publications

(100 citation statements)

References 57 publications

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Section: Findings From Scid Newborn Screening In Californiamentioning

confidence: 99%

“…Finally, population‐based screening for insufficient T cells provides the opportunity to discover new genetic defects of T cell immunity, revealing information about T cell developmental pathways that are important in humans. Mutations in BCL11B and EXTL3 were newly discovered T cell deficiency diseases following NBS in California; infants detected by screening who lacked defects in known SCID genes were enrolled in research protocols to undergo exome sequencing and functional analysis of variants. Population‐based detection of SCID and non‐SCID TCL by TREC screening will undoubtedly continue to reveal infants with new genes and immuno‐developmental pathways that are essential for human T cell development.…”

Section: Lessons From Scid Newborn Screeningmentioning

confidence: 99%

“…One infant with CHARGE syndrome was considered for thymus transplantation, but died of respiratory failure. Single patients with very rare conditions constituted the remainder of cases with syndromes, including one with a novel short-limbed immuno-skeletal dysplasia in whom whole exome sequencing revealed EXTL3 deficiency 48 and one with RAC2 mutation as described in a single previous case. 49 Secondary TCL in 25 cases (Figure 4) had T-cell suppression due to in utero exposure to maternal medications, fingolimod and azathioprine, respectively, and one infant had a thymic teratoma, with T cells normalizing after it was resected.…”

Section: Non-scid T-cell Lymphopeniamentioning

confidence: 99%

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Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Puck

2018

Immunological Reviews

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121

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Summary The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots made possible universal newborn screening (NBS) for severe combined immunodeficiency (SCID) as a public health measure. Upon being flagged by an abnormal screening test in a SCID screening program, an infant can receive further diagnostic testing for SCID in the neonatal period, prior to onset of infectious complications, to pemit immediate institution of protective measures and definitive, life-saving treatment to establish a functional immune system. SCID screening is now the accepted standard of care in state public health departments across the USA, and it is being adopted in many countries. It has proven effective, with infants having this otherwise inapparent but serious, rare disorder achieving survival and immune reconstitution. In addition to bringing to attention infants with the primary screening target diseases, typical SCID and leaky SCID (due to hypomorphic mutations in known SCID genes), the newborn screening assay for insufficient TRECs in dried blood spots also reveals infants with non-SCID T lymphopenic conditions. Experience has accumulated regarding the range and limitations of diagnoses of newborns with low TRECs and low T cells. Previously unknown immune defects have been discovered, as well as conditions not formerly recognized to have low T cells in the neonatal period.

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Section: Findings From Scid Newborn Screening In Californiamentioning

confidence: 99%

Section: Lessons From Scid Newborn Screeningmentioning

confidence: 99%

Section: Non-scid T-cell Lymphopeniamentioning

confidence: 99%

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Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Puck

2018

Immunological Reviews

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121

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“…In EXTL3 ‐deficient cells, reduced HS synthesis coupled to increased CS and DS synthesis have been observed . Moreover, in these patients HS chains were longer and abnormally sulfated compared to controls .…”

Section: Intracellular and Extracellular Consequences Of The Defects mentioning

confidence: 99%

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

et al. 2019

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Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides that constitute the carbohydrate moiety covalently attached to the protein core of proteoglycans, macromolecules present on the cell surface and in the extracellular matrix. Several genetic disorders of bone and connective tissue are caused by mutations in genes encoding for glycosyltransferases, sulfotransferases and transporters that are responsible for the synthesis of sulfated GAGs. Phenotypically, these disorders all reflect alterations in crucial biological functions of GAGs in the development, growth and homoeostasis of cartilage and bone. To date, up to 27 different skeletal phenotypes have been linked to mutations in 23 genes encoding for proteins involved in GAG biosynthesis. This review focuses on recent genetic, molecular and biochemical studies of bone and connective tissue disorders caused by GAG synthesis defects. These insights and future research in the field will provide a deeper understanding of the molecular pathogenesis of these disorders and will pave the way for developing common therapeutic strategies that might be targeted to a range of individual phenotypes.

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“…Recently, exostosinlike glycosyltransferase 3 (EXTL3) that regulates the biosynthesis of heparan sulphate (HS) and is important for both skeletal development and haematopoiesis has been linked to distinct clinical phenotype by two groups. EXTL3 mutations are responsible for "neuro-immuno-skeletal dysplasia syndrome" with variable skeletal abnormalities, neurodevelopmental defects and combined immunodeficiency (Oud et al, 2017;Volpi et al, 2017).…”

Section: )mentioning

confidence: 99%

Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

et al. 2017

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Abstract:Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations in EXT1 and EXT2 genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA in EXT1 and EXT2 genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2-10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient

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EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay

Cited by 72 publications

References 57 publications

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

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