The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization.
SUMMARY Twenty-nine members of an extended Arab family from the Gaza Strip were found to be affected with cone-rod dystrophy and amelogenesis imperfecta, inherited in an autosomal recessive manner. Medical historyAll affected members suffered from photophobia and nystagmus, starting in the first two years of life, and achromatopsia. There was no night blindness.All dentate members had abnormal, discoloured teeth. Clinical examination ' 5 :OCULAR Visual acuities ranged from 6/36 to no perception of light, and a marked pendular nystagmus was present in all cases. The earliest fundus abnormality, observed in both eyes of a three month old child, was a round area of retinal pigment epithelial atrophy at the macula giving rise to an early bull's eye appearance.
A consanguineous Arab pedigree in which recessive amelogenesis imperfecta (AI) and cone-rod dystrophy cosegregate, was screened for linkage to known retinal dystrophy and tooth abnormality loci by genotyping neighbouring microsatellite markers. This analysis resulted in linkage with a maximum lod score of 7.03 to the marker D2S2187 at the achromatopsia locus on chromosome 2q11, and haplotype analysis placed the gene(s) involved in a 2 cM/5 Mb interval between markers D2S2209 and D2S373. The CNGA3 gene, known to be involved in achromatopsia, lies in this interval but thorough analysis of its coding sequence revealed no mutation. Furthermore, affected individuals in four consanguineous recessive pedigrees with AI but without CRD were heterozygous at this locus, excluding it as a common cause of non-syndromic recessive AI. It remains to be established whether this pedigree is segregating two closely linked mutations causing disparate phenotypes or whether a single defect is causing pathology in both teeth and eyes.
SUMMARY Two female cousins were found to be affected with severe retinal dystrophy characterised by visual impairment from birth and profound photophobia in the absence of night blindness. Minimal fundus changes with a small foveal atrophy in the older cousin and slight macular pigment epithelial changes suggestive of early bull's eye appearance in the younger were detected, indicative of a cone-rod type of congenital amaurosis. This was associated with trichomegaly, bushy eyebrows with synophyrys, and excessive facial and body hair (including hypertrophied circumareolar hair on the breasts of the older cousin). The mode of inheritance appears to be autosomal recessive.Congenital blindness from a retinal dystrophy was first reported by Leber' in 1869 when he described a 'pigmentary retinopathy with congenital amaurosis'.He also recognised the familial nature of the condition and the role of consanguinity.2 Leber's congenital amaurosis represents a heterogeneous group of genetically determined conditions which share in common severe visual impairment at birth, or in the first year of life, coarse nystagmus, unrecordable electroretinogram, and variable age of onset of retinal and pigmentary degeneration, rather than a syndrome with different nosological entities as was believed by Krill and other workers.3" Excessively long eyelashes, large and bushy eyebrows with synophrys, and hypertrophied lanugo covering the entire body with a moustache and beard was reported by Broster5 in 1950 and is known as congenital generalised hypertrichosis. Gray6 in 1944 ascribed the term trichomegaly or 'movie lashes' to these abnormally long lashes.The following two cases show an unusual combination of Leber's amaurosis and cone-rod dystrophy and congenital hypertrichosis (fig 1). Patients and methodsThe two cases, aged 18 and 121½2 years when first examined, are maternal first cousins who were reviewed
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.