The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies.

Petzold F, Billot K, Chen X, Henry C, Filhol E, Martin Y, Avramescu M, Douillet M, Morinière V, Krug P, Jeanpierre C, Tory K, Boyer O, Burgun A, Servais A, Salomon R, Benmerah A, Heidet L, Garcelon N, Antignac C, Zaidan M, Saunier S, Attié-Bitach T, Comier-Daire V, Rozet JM, Frishberg Y, Llanas B, Broyer M, Mohsin N, Macher MA, Philip N, Baudouin V, Brackman D, Loirat C, Charbit M, Dehennault M, Guyot C, Bataille P, Elting M, Deschenes G, Gropman A, Guest G, Gagnadoux MF, Nicoud P, Cochat P, Ranchin B, Bensman A, Guerrot AM, Knebelmann B, Bilge I, Bruno D, Burtey S, Rouvière CR, Caudwell V, Morin D, Dollfus H, Maisin A, Hamel C, Bieth E, Gie S, Goodship J, Roussey G, La Selve H, Nivet H, Bessenay L, Caillez M, Palcoux JB, Benoît S, Dubot P, Fila M, Giuliano F, Iftene D, Kessler M, Kwon T, Lahoche A, Laurent A, Leclerc AL, Milford D, Neuhaus T, Odent S, Eckart P, Chauveau D, Niaudet P, Repetto H, Taque S, Bruel A, Noel-Botte A, Launay EA, Allard L, Anlicheau D, Adra AL, Garnier A, Nagra A, Baatard R, Bacchetta J, Sadikoglu B, Barnerias C, Barthelemy A, Basel L, Bassilios N, Ben Maiz H, Ben Moussa F, Benmati F, Berthaud R, Bertholet A, Blanchier D, Boffa JJ, Bouchireb K, Bouhabel I, Boukerroucha Z, Bourdat-Michel G, Boute O, Brochard K, Caumes R, Elalaoui SC, Chamontin B, Chastang MC, Pietrement C, Richer C, Legendre C, Dahan K, Dalla-Vale F, Thibaudin D, Dauvergne M, Davourie S, Debeukelaer M, Delbet JD, Deltas C, Graber D, Devillars N, Diouf B, Fenzy MD, André JL, Joly D, Fryer A, Albano L, Cassuto E, Pincon A, Medeira A, Chaussenot A, Mensire-Marinier A, Bouissou F, Decramer S, Bottani A, Hummel A, Karras A, Katz A, Azema C, Janbon B, Roussel B, Bonniol C, Mariat C, Champion G, Chantreuil D, Chassaing N, Mousson C, Baudeau C, Cuntz DH, Mignot C, Dehoux L, Lacombe D, Hannedouche T, Mérieau E, Charlin E, Gauthier E, Plasse F, Faguer S, Lebas F, Demurger F, Emma F, Cartault F, Dumont G, Godefroid N, Guigonis V, Hillaire S, Groothoff J, Dudley J, Jourde-Chiche N, El Karoui K, Krid S, Coudert K, Bencheick L, Yver L, Lavocat MP, De Sagazan LM, Leroy V, Thibaudin L, Ingulli L, Gwanmesia L, Burglen L, Saïd-Menthon MH, Carrera M, Nizon M, Melander C, Foulard M, Blayo M, Prinseau J, Jay N, Brun N, Camille N, Nobili F, Devuyst O, Ben Brahim O, Parvex P, Sabourin LP, Blanc P, Vanhille P, Galichon P, Pierrepont S, Planquois V, Poussard G, Noble CP, Allal R, Bernard R, Mounet R, Cahen R, Touraine R, Rigothier C, Ryckewaert A, Sacquepee M, El Chehadeh S, Samaille C, Haq S, Simckes A, Lanoiselée S, Tellier S, Subra JF, Cloarec S, Tenenbam J, Lamy T, Garraud VD, Valette H, Meyssonnier V, Vargas-Poussou R, Snajer Y, Durault S, Plaisier E, Berard E, Fakhouri F, Louillet F, Finielz P, Fischbach M, Foliguet B, Francois-Pradier H, Garaix F, Gerard M, Rizzoni G, Gilbert B, Glotz D, Dubrasquet AG, Grünfeld JP, Bollee G, Hall M, Hansson S, Haye D, Taffin H, Hildebrandt F, Hourmand M, Kayserili H, Tack I, Jacquemont ML, Fabre-Teste J, Kashtan C, Van Hoeck K, Klein A, Knefati Y, Knoers N, Konrad M, Lachaux A, Landru I, Landthaler G, Lang P, Le Pogamp P, Legris T, Didailler C, Lobbedez T, de Parscau L, Pinson L, Maheut H, Duval-Arnould M, Rio M, Gubler MC, Merville P, Mestrallet G, Meunier M, Moreau K, Harambat J, Morgan G, Mourad G, Stuber N, Boespflug-Tanguy O, Dunand O, Niel O, Ouali N, Malvezzi P, Jaoude PA, Pelletier S, Peltier J, Petersen MB, Michel P, Rémy P, Philit JB, Pichault V, Billette de Villemeur T, Boudailliez B, Leheup B, Dossier C, Djeddi DD, Berland Y, Hurault de Ligny B, Rigden S, Robino C, Rossi A, Sarnacki S, Saidani M, Sartorius AB, Schäfer E, Laszlo S, Thouret MC, Thuillier-Lecouf A, Trachtman H, Trivin C, Tsimaratos M, Van Damme-Lombaerts R, Willems M, Youssef M, Zaloszyc A, Zawodnik A, Ziliotis MJ.

Source :

Kidney Int

2023 Aug 1

Pmid / DOI:

37230223

Abstract

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

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