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A novel JAG1 mutation causing Alagille syndrome presenting with giant hepatic nodules and discordant phenotype in monozygotic twins
Yi Zhanga, Bo Xiangb, Xijie Yua,
Corresponding author
a Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
b Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Alagille syndrome &#40;ALGS&#41; is a rare autosomal dominant genetic disorder with multisystem organ involvement&#46; Pathogenic variants in the genes encoding Jagged1 &#40;<span class="elsevierStyleItalic">JAG1</span>&#41; and Notch 2 &#40;<span class="elsevierStyleItalic">NOTCH2</span>&#41; in the Notch signaling pathway have been identifiedOda&#44; Elkahloun&#44; Pike&#44; Okajima&#44; Krantz&#44; Genin&#44; Piccoli&#44; Meltzer&#44; Spinner&#44; Collins&#44; Chandrasekharappa&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> The clinical diagnosis can be made in the presence of bile duct paucity&#44; along with 3 or more of the following major features&#58; chronic cholestasis&#44; cardiac defects&#44; skeletal abnormalities&#44; ocular abnormalities and characteristic facies&#46; Nevertheless&#44; the widely variable phenotype in ALGS raises questions about the primary role of the genotype in giving rise to features&#44; or whether at least some of the effects are secondary to nongenetic factors&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">This was a pair of monochorionic female twins born after 34 weeks of gestation&#46; The family history was unremarkable&#44; and there was no history of consanguinity&#46; Twin A presented with intermittent pruritus and stomachache at 10 years old&#46; Twin B had similar but less prominent symptoms&#46; Twin A weighed 23&#46;5<span class="elsevierStyleHsp" style=""></span>kg &#40;&#8722;1&#46;93SD&#41; and height was 129&#46;5<span class="elsevierStyleHsp" style=""></span>cm &#40;&#8722;2&#46;15SD&#41;&#46; Pertinent physical findings included pointed chin&#44; deep set eyes&#44; short nose&#44; triangular face&#44; broad forehead&#46; Laboratory tests revealed elevated liver function test markers&#46; Computed tomography showed butterfly vertebrae of T8&#44; lack of left kidney&#44; an 8&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>6&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>9&#46;5<span class="elsevierStyleHsp" style=""></span>cm lesion located in the right trisegment of the liver&#46; A hepatic biopsy showed absence of bile duct&#46; Ophthalmologic examination showed posterior embryotoxon in the right eye&#46; An echocardiogram was normal&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The weight of Twin B was 23<span class="elsevierStyleHsp" style=""></span>kg &#40;&#8722;2&#46;08SD&#41; and her height was 129<span class="elsevierStyleHsp" style=""></span>cm &#40;&#8722;2&#46;23SD&#41;&#46; She had the same characteristic face as Twin A&#46; Impairment in her liver function was detected&#46; Computed tomography showed a 8&#46;1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>9&#46;0<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>7&#46;7<span class="elsevierStyleHsp" style=""></span>cm lesion located in the right trisegment of the liver&#46; No vertebral and renal abnormalities were detected&#46; Ophthalmologic examination revealed posterior embryotoxon in the left eye&#46; Cardiac ultrasonography revealed a thickening of the coronary sinus of approximately 11<span class="elsevierStyleHsp" style=""></span>cm&#46; The clinical information of the twins and the mother is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The genetic testing revealed a heterozygous variant in the <span class="elsevierStyleItalic">JAG1</span> gene&#44; p&#46;G934Vfs&#42;11 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The frameshift mutation in the 23rd exon of <span class="elsevierStyleItalic">JAG1</span> &#40;c&#46;2801&#95;c&#46;2802delGCinsT&#59; p&#46; G934Vfs&#42;11&#41; in both twins was inherited from their mother&#44; while the <span class="elsevierStyleItalic">JAG1</span> gene in their father was wild type&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">To our knowledge&#44; this is the third observation of monozygotic twins with ALGS&#46; Due to the widely variant phenotype of ALGS&#44; it is quite confused about which factors contributing to the developmental defects of organs&#46; Since monozygotic twins are believed to have identical genetic information&#44; we could find some clues combining the three cases of monozygotic twins with ALGS&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Chronic cholestasis occurs in a very high proportion &#40;&#8764;95&#37;&#41; of cases&#44; and most commonly&#44; presents in the neonatal period or first 3 months of life&#44; with jaundice due to conjugated hyperbilirubinemia&#46; In the three pairs of monozygotic twins&#44; all of them had liver involvement but with different severity&#46; Notch signaling is tightly linked with the development of bile ducts&#46; Izumi et al&#46; proposed the fetal hypoxia may modify the liver disease severity of ALGS in monozygotic twins&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> Animal studies revealed that the Fringe genes including Lunatic &#40;<span class="elsevierStyleItalic">Lfng</span>&#41;&#44; Radical &#40;<span class="elsevierStyleItalic">Rfng</span>&#41;&#44; and Manic &#40;<span class="elsevierStyleItalic">Mfng</span>&#41; may regulate postnatal bile duct growth and remodeling&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> Hence&#44; <span class="elsevierStyleItalic">JAG1</span> mutations largely cause the liver phenotype of ALGS&#44; while environmental factors and genetic modifiers may affect the phenotypic severity&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">More than 90&#37; ALGS patients have cardiovascular anomalies and characteristic facies&#46; Three pairs of twins had facial features and five patients had cardiac defects&#44; highlighting roles of Jag1 in the heart development&#46; The cause of the facies has been debatable&#46; It has been proposed that the facial dysmorphism is secondary to congenital intrahepatic cholestasis while Kamath et al&#46; implied it was specific but not a common endpoint of cholestasis&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> Interestingly&#44; renal anomalies occurred in almost half of twins&#46; The role of <span class="elsevierStyleItalic">NOTCH2</span> and <span class="elsevierStyleItalic">JAG1</span> in formation of proximal tubules and podocytes might explain the renal dysplasia and proteinuria&#46; Further researches are needed on how specific human mutations lead to kidney defects&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">It is a very complex process how JAG1 mutations lead to multisystem defects through the Notch signaling pathway&#44; also environmental factors and genetic modifiers should be considered&#46; Further efforts into understanding the transcriptional control of Notch genes will be essential for deciphering how variable mutations affect gene regulation and impact on disease&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical features and genetic results in the family of monozygotic twins&#46; &#40;a&#41; Facial dysmorphism of twins and the mother&#46; &#40;b&#41; Posterior embryotoxon &#40;black arrow&#41; in eyes of Ttwin A and Twin B&#44; the mother had normal eyes&#46; &#40;c&#41; A similar giant liver lesion is present in twins&#46; &#40;d&#41; Butterfly vertebra &#40;white arrow&#41; in T8 of Twin A&#46; &#40;e&#41; Single kidney of Twin A&#46; &#40;f&#41; Chromatogram showing genetic mutation &#40;c&#46;2801&#95;c&#46;2802delGCinsT&#59; p&#46; G934Vfs&#42;11&#41;&#46;</p>"
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            0 => array:3 [
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                  "contribucion" => array:1 [
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                      ]
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                  ]
                  "host" => array:1 [
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            1 => array:3 [
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                      "autores" => array:1 [
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                          "autores" => array:5 [
                            0 => "B&#46;M&#46; Kamath"
                            1 => "I&#46;D&#46; Krantz"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ajmg.10610"
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                    ]
                  ]
                ]
              ]
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            2 => array:3 [
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              "etiqueta" => "3"
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                  "contribucion" => array:1 [
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                      "titulo" => "Discordant clinical phenotype in monozygotic twins with Alagille syndrome&#58; possible influence of non-genetic factors"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Izumi"
                            1 => "D&#46; Hayashi"
                            2 => "C&#46;M&#46; Grochowski"
                            3 => "N&#46; Kubota"
                            4 => "E&#46; Nishi"
                            5 => "M&#46; Arakawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "fecha" => "2016"
                        "volumen" => "170"
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                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bile duct proliferation in Jag1&#47;fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;J&#46; Ryan"
                            1 => "C&#46; Bales"
                            2 => "A&#46; Nelson"
                            3 => "D&#46;M&#46; Gonzalez"
                            4 => "L&#46; Underkoffler"
                            5 => "M&#46; Segalov"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22538"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "48"
                        "paginaInicial" => "1989"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19026002"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Facial features in Alagille syndrome&#58; specific or cholestasis facies&#63;"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;M&#46; Kamath"
                            1 => "K&#46;M&#46; Loomes"
                            2 => "R&#46;J&#46; Oakey"
                            3 => "K&#46;E&#46; Emerick"
                            4 => "T&#46; Conversano"
                            5 => "N&#46;B&#46; Spinner"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ajmg.10579"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med Genet"
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        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0045" class="elsevierStylePara elsevierViewall">The authors appreciate the efforts of Dr&#46; Kewei Li for assistance of the case&#46; This work was supported by grants from the <span class="elsevierStyleGrantSponsor" id="gs1">National Natural Science Foundation of China</span> &#40;Nos&#46; <span class="elsevierStyleGrantNumber" refid="gs1">81770875</span>&#44; <span class="elsevierStyleGrantNumber" refid="gs1">81572639</span>&#41;&#44; the <span class="elsevierStyleGrantSponsor" id="gs2">Science and Technology Department of Sichuan Province</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs2">2018SZ0142</span>&#41;&#44; and <span class="elsevierStyleGrantSponsor" id="gs3">Sichuan University</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs3">2018SCUH0093</span>&#41;&#46;</p>"
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ISSN: 00257753
Original language: English
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