RESUMO
PURPOSE: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.
Assuntos
Carboxiliases/genética , Carboxiliases/metabolismo , Adolescente , Adulto , Brasil , Exoma/genética , Feminino , Genótipo , Células HEK293 , Perda Auditiva Neurossensorial/genética , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Anormalidades Musculoesqueléticas/genética , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Portugal , Degeneração Retiniana/genética , Síndrome , Adulto JovemRESUMO
PURPOSE: We describe the clinical phenotype of a Mexican family segregating Duane syndrome as an autosomal-dominant trait linked to chromosome 2q31 (DURS2) and previously reported to harbor a heterozygous alpha2-chimaerin missense mutation. METHODS: A 5-generation Mexican family was analyzed. Ten affected subjects were available for clinical examination. Participating subjects were tested for visual acuity, ocular alignment by prism cover testing, ocular ductions and versions, and globe retraction. In children, alignment was measured with the Krimsky test in cardinal positions of gaze. RESULTS: Ten cases were included, 6 female and 4 male subjects. Five cases presented with bilateral and 5 with unilateral Duane syndrome. The right side was the most commonly affected side on unilateral cases. Five cases exhibited exotropia, 4 esotropia, and 1 hypotropia. Seven patients had severe limitation of abduction and two had moderate limitation. Four patients had mild adduction limitation and 4 had moderate limitation. No additional anomalies such as fourth (trochlear) nerve palsy, blepharoptosis, or dense amblyopia, which have been reported in previous families with Duane syndrome, were observed. All 3 cases that exhibited vertical dysfunction had upgaze limitation. One instance of nonpenetrance was recorded. CONCLUSIONS: Considerable intrafamilial clinical variability was observed in this Duane syndrome pedigree that carried a alpha2-chimaerin mutation. The presence of bilateral involvement and associated vertical movements, which commonly are observed in this and other DURS2 families, could suggest the occurrence of CHN1 mutations as the source of the disease in isolated or familial DURS cases.
Assuntos
Quimerina 1/genética , Síndrome da Retração Ocular/genética , Mutação Puntual , Adolescente , Adulto , Pré-Escolar , Síndrome da Retração Ocular/fisiopatologia , Movimentos Oculares , Saúde da Família , Feminino , Genes Dominantes , Humanos , Masculino , México , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
Objetivo: Correlacionar tipo clínico de fibrosis muscular congénita (CFEOM tipo 1) y falla genética en los miembros afectados en tres generaciones de una familia chilena. Metodología: enrolamiento de portadores de fibrosis muscular congénita tipo clínico 1 (CFEOM 1) según protocolo. Fotografía y video, pedigrí familiar, obtención de muestra de sangre, extracción del DNA linfositario de casos/control, Linkage análisis de DNA. Resultados: Identificación de mutación AD en cromosoma 11, gen KIF21A en todos los afectados en una familia con tres generaciones con CFEOM tipo 1. Codifica proteína motora kinesina, que participa en el desarrollo del III par craneal. Conclusiones: En este tipo de estrabismo la alteración primaria es inervacional y no muscular. Relación entre forma clínica y cromosoma afectado permite caracterizar genéticamente las distintas formas clínicas de la enfermedad. Se propone una clasificación clínica nueva de los estrabismos restrictivos congénitos.
Aim: To correlate a clinical type of congenital muscular fibrosis (CFEOM type 1) with a genetic flaw in the affected members of three generations of a single Chilean family. Methods: Clinical type 1 congenital muscular fibrosis carriers were enrolled according to protocol. For each patient, the following information was collected: Video and pictures, family pedigree, blood samples, case/ control lymphocytes DNA, and DNA linkage analysis. Results: An AD mutation in chromosome 11 was identified. KIF21A gene was found in all affected members of the family over the three generations. It codified The motor protein kinesin, which is involved in the development of the third cranial nerve. Conclusions: In this form of strabismus, the primary dysfunction is innervational rather than muscular. The relationship between the clinical form and the affected chromosome permits identification of the various clinical forms of the disease. We propose a new clinical classification of the congenital restrictive strabismus.