Advanced

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders

Travaglini, Lorena; Brancati, Francesco; Silhavy, Jennifer; Iannicelli, Miriam; Nickerson, Elizabeth; Elkhartoufi, Nadia; Scott, Eric; Spencer, Emily; Gabriel, Stacey and Thomas, Sophie, et al. (2013) In European Journal of Human Genetics 21(10). p.8-1074
Abstract

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD... (More)

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Abnormalities, Multiple, Adolescent, Amino Acid Sequence, Cerebellar Diseases, Cerebellum, Child, Child, Preschool, Ciliary Motility Disorders, Encephalocele, Eye Abnormalities, Female, Gene Frequency, Heterozygote, Humans, Infant, Kidney Diseases, Cystic, Male, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Phosphoric Monoester Hydrolases, Polycystic Kidney Diseases, Prenatal Diagnosis, Prevalence, Retina, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
in
European Journal of Human Genetics
volume
21
issue
10
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:84884592278
ISSN
1476-5438
DOI
10.1038/ejhg.2012.305
language
English
LU publication?
yes
id
b72d3f4c-ec50-4ddf-b7da-3af6ff251820
date added to LUP
2017-07-04 15:47:15
date last changed
2018-11-21 21:33:14
@article{b72d3f4c-ec50-4ddf-b7da-3af6ff251820,
  abstract     = {<p>Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.</p>},
  author       = {Travaglini, Lorena and Brancati, Francesco and Silhavy, Jennifer and Iannicelli, Miriam and Nickerson, Elizabeth and Elkhartoufi, Nadia and Scott, Eric and Spencer, Emily and Gabriel, Stacey and Thomas, Sophie and Ben-Zeev, Bruria and Bertini, Enrico and Boltshauser, Eugen and Chaouch, Malika and Cilio, Maria Roberta and de Jong, Mirjam M and Kayserili, Hulya and Ogur, Gonul and Poretti, Andrea and Signorini, Sabrina and Uziel, Graziella and Zaki, Maha S and Johnson, Colin and Attié-Bitach, Tania and Gleeson, Joseph G and Valente, Enza Maria and ,  and Puschmann, Andreas},
  issn         = {1476-5438},
  keyword      = {Abnormalities, Multiple,Adolescent,Amino Acid Sequence,Cerebellar Diseases,Cerebellum,Child,Child, Preschool,Ciliary Motility Disorders,Encephalocele,Eye Abnormalities,Female,Gene Frequency,Heterozygote,Humans,Infant,Kidney Diseases, Cystic,Male,Molecular Sequence Data,Mutation,Pedigree,Phenotype,Phosphoric Monoester Hydrolases,Polycystic Kidney Diseases,Prenatal Diagnosis,Prevalence,Retina,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {10},
  pages        = {8--1074},
  publisher    = {Nature Publishing Group},
  series       = {European Journal of Human Genetics},
  title        = {Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders},
  url          = {http://dx.doi.org/10.1038/ejhg.2012.305},
  volume       = {21},
  year         = {2013},
}