title: Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations.
abstract: Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter- and intra-familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra-familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well-known disease-associated genes, using reverse phenotyping.
authors.affiliation: Service de p, é, diatrie 1 et de génétique médicale, Centre Hospitalo-Universitaire, Dijon, France.|Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Jean-Benoît
authors.initials: JB
authors.lastname: Courcet
authors.affiliation: Service d'hépato-gastro-entérologie, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Minello
authors.affiliation: Service De Génétique Clinique Chromosomique et Moléculaire, Pole De Biologie, Centre Hospitalo-Universitaire De Saint-Etienne - H, ô, pital Nord, Avenue Albert Raimond, Saint-Priest-En-Jarez, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Prieur
authors.affiliation: Service de médecine polyvalente, Hôpital de SIA, Wallis et Futuna, Uvea, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Morisse
authors.affiliation: Service d'Hépato-gastro-entérologie, Centre Hospitalo-Universitaire, Sant-Etienne, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Phelip
authors.affiliation: Service de chirurgie, Hôpital de SIA, Wallis et Futuna, Uvea, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Beurdeley
authors.affiliation: Laboratoire de biologie médicale, Hôpital de SIA, Wallis et Futuna, Uvea, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Meynard
authors.affiliation: Laboratoire de biologie médicale, Hôpital de SIA, Wallis et Futuna, Uvea, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Massenet
authors.affiliation: Service de Médecine Interne, Hôpital Magenta, Nouméa, France.
authors.forename: Flore
authors.initials: F
authors.lastname: Lacassin
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.|Laboratoire de biologie moléculaire, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.|Laboratoire de biologie moléculaire, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Gigot
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.|Laboratoire de biologie moléculaire, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Judith
authors.initials: J
authors.lastname: St-Onge
authors.affiliation: Service d'hépato-gastro-entérologie, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hillon
authors.affiliation: Service de gastro-entérologie et hépatologie, Hôpital Jean Minjoz, Centre Hospitalo-Universitaire, Besançon, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Vanlemmens
authors.affiliation: Service de néphrologie, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mousson
authors.affiliation: Service de radiologie, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cerceuil
authors.affiliation: Service de radiologie, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Guiu
authors.affiliation: Service de p, é, diatrie 1 et de génétique médicale, Centre Hospitalo-Universitaire, Dijon, France.|Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Service de p, é, diatrie 1 et de génétique médicale, Centre Hospitalo-Universitaire, Dijon, France.|Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: Service d'hépatologie pédiatrique, Centre Hospitalo-Universitaire, Le Kremlin-Bic, ê, tre, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.|Laboratoire de biologie moléculaire, Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: Service d'endocrinologie moléculaire et maladies rares, Centre de Biologie et Pathologie Est CHU de Lyon-GH Est, Hospices Civils de Lyon, Bron, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Michel-Calemard
authors.affiliation: Service de p, é, diatrie 1 et de génétique médicale, Centre Hospitalo-Universitaire, Dijon, France.|Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalo-Universitaire, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D000328:Adult; D001649:Bile Duct Diseases / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics*; D055815:Young Adult
chemical_list: C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface
keywords: Caroli disease; PKHD1; autosomal recessive polycystic kidney disease; ductal plate malformation