A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance

Ali, Silhavy, Akawi, Gleeson, Al-Gazali, Al-Gazali Lihadh

Description

We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. Methods In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Results Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia. Conclusions We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.

Sujets

• Joubert
• Sonic hedgehog
• Dysmorphic feature
• Multiple epiphyseal dysplasia

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 390
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Aliet al. Orphanet Journal of Rare Diseases2012,7:27 http://www.ojrd.com/content/7/1/27

R E S E A R C HOpen Access A mutation inKIF7is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance 1 21 23* Bassam R Ali , Jennifer L Silhavy , Nadia A Akawi , Joseph G Gleesonand Lihadh AlGazali

Abstract Background:We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. Methods:In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Results:Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia. Conclusions:We report the first missense homozygous diseasecausing mutation inKIF7and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients. Keywords:KIF7, Acrocallosal, Joubert, Sonic hedgehog, Dysmorphism, Multiple epiphyseal dysplasia, Fetal hydrolethalus

Background Multiple epiphyseal dysplasia (MED) is a clinical con dition characterized by a defect in the process of ossi fication through mineralization of cartilage. Patients typically present after age two years with joint pain, skel etal abnormalities and short stature. Radiographic in vestigations point to a generalized delay in epiphyseal ossification together with changes in epiphyseal contour. The range of severity of both clinical and radiographic presentations can be quite striking. Affected joints can include long bones and tubular bones (metacarpals, metatarsals and phalanges), whereas vertebral bodies are

* Correspondence: [e-mail] 3 Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, AlAin, United Arab Emirates Full list of author information is available at the end of the article

only rarely affected [1]. Both dominant and recessive gen etic forms exist and can have similar presentations [2]. TheKIF7gene was first identified as encoding a mem ber of the KIF27 family of kinesin motor domain con taining microtubule plusend directed motors [3]. The KIF27 family in mammals consists of at least 5 mem bers, all with homology to Drosophila Costal2 protein [3]. All members were found to be implicated in Hedge hog signaling (Hh). However, KIF7 implication in Hh sig naling in vertebrates has not been straightforward [4]. Through genetic interaction,KIF7gene has been recently shown to be causing Joubert syndrome and the spectrum of fetal hydrolethalus and acrocallosal syndromes [5,6]. Joubert syndrome (JBTS, MIM#213300) is a polygenic condition characterized by a pathognomonic midline “molar tooth”on brain magnetic resonance imaging

© 2012 Ali et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.