title: Nonsyndromic Early-Onset Cone-Rod Dystrophy and Limb-Girdle Muscular Dystrophy in a Consanguineous Israeli Family are Caused by Two Independent yet Linked Mutations in ALMS1 and DYSF.
abstract: Genetic analysis of clinical phenotypes in consanguineous families is complicated by coinheritance of large DNA regions carrying independent variants. Here, we characterized a family with early onset cone-rod dystrophy (CRD) and muscular dystrophy. Homozygosity mapping (HM) followed by whole exome sequencing revealed a nonsense mutation, p.R270*, in ALMS1 and two novel potentially disease-causing missense variants, p.R1581C and p.Y2070C, in DYSF. ALMS1 and DYSF are genetically and physically linked on chromosome 2 in a genomic region suggested by HM and associated with Alström syndrome, which includes CRD, and with limb girdle muscular dystrophy, respectively. Affected family members lack additional systemic manifestations of Alström syndrome but exhibit mild muscular dystrophy. RNA-seq data did not reveal any significant variations in ALMS1 transcripts in the human retina. Our study thus implicates ALMS1 as a nonsyndromic retinal disease gene and suggests a potential role of variants in interacting cilia genes in modifying clinical phenotypes.
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland.|Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano Sciences, Babes-Bolyai-University, Cluj-Napoca, Romania.
authors.forename: Csilla H
authors.initials: CH
authors.lastname: Lazar
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Kimchi
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Namburi
authors.affiliation: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, India.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Mutsuddi
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland.|Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avigail
authors.initials: A
authors.lastname: Beryozkin
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Ben-Simhon
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Alexey
authors.initials: A
authors.lastname: Obolensky
authors.affiliation: Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ziva
authors.initials: Z
authors.lastname: Ben-Neriah
authors.affiliation: Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Argov
authors.affiliation: Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.affiliation: Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yakov
authors.initials: Y
authors.lastname: Fellig
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Devorah
authors.initials: D
authors.lastname: Marks-Ohana
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rinki
authors.initials: R
authors.lastname: Ratnapriya
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D018797:Cell Cycle Proteins; D003241:Consanguinity; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012160:Retina / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*
chemical_list: C490729:ALMS1 protein, human; D018797:Cell Cycle Proteins; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D011506:Proteins
keywords: ALMS1; DYSF; photoreceptor; pleiotropic phenotypes; retinal degeneration; vision loss