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Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity.

ABSTRACT: In daily life, myopia is a frequent cause of reduced visual acuity (VA) due to missing or incomplete optical correction. While the genetic cause of high myopia itself is not well understood, a significant number of cases are secondary to hereditary malfunctions or degenerations of the retina. The mechanism by which this occurs remains yet unclear. Two female siblings, 4?y and 2?y, respectively, from a consanguineous Pakistani family were referred to our department for reduced VA and strabismus. Both girls were highly myopic and hence were further examined using standard clinical tests and electroretinography (ERG). The latter confirmed confounded electrical coupling of photoreceptors and bipolar cells. Further inquiry and testing confirmed a similar condition for the father including impaired night vision, reduced VA, photophobia, and an equally characteristic ERG. Findings in the mother were unremarkable. Subsequent genetic analysis of autosomal recessive and X-linked genes for congenital stationary night blindness (CSNB) revealed a novel homozygous splice site mutation in CACNA1F in the two girls transmitted from both the father and the mother. While in males the above clinical constellation is a frequent finding, this report, to the authors' knowledge, is the first demonstrating biallelic mutations at the CACNA1F locus in females.

SUBMITTER: Preising MN

PROVIDER: S-EPMC6116399 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity.

Preising M N MN Friedburg C C Bowl W W Lorenz B B

BioMed research international 20180523

In daily life, myopia is a frequent cause of reduced visual acuity (VA) due to missing or incomplete optical correction. While the genetic cause of high myopia itself is not well understood, a significant number of cases are secondary to hereditary malfunctions or degenerations of the retina. The mechanism by which this occurs remains yet unclear. Two female siblings, 4 y and 2 y, respectively, from a consanguineous Pakistani family were referred to our department for reduced VA and strabismus. ...[more]

PMID: 30186847

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Project description:To identify genetic mutations in three families with early onset high myopia (eoHM) limited to female members.Genomic DNA was collected from participating members of families XF1, XF2, and XF3. Genome-wide linkage scans were performed on the largest family (XF1). Whole exome sequencing was performed on seven samples, including five samples (four affected and one unaffected) from family XF1, as well as the two probands from family XF2 and XF3. Variants were analyzed with multistep bioinformatics analyses. Sanger-dideoxy sequencing was used to verify candidate variations in families and controls.The genome-wide linkage scans performed on family XF1 detected a candidate locus on chromosome Xp11.1-Xq13.3 with a maximum logarithm of the odds (LOD) score of 2.48 and 3.01 for markers DXS991 and DXS986, respectively. Parallel whole exome sequencing identified a novel c.893C>A (p.Ala298Asp) mutation in ARR3 located on Xq13.1 in family XF1, which was shared by all four affected individuals but not the unaffected individual. Two other novel mutations in ARR3, c.298C>T (p.Arg100*) and c.239T>C (p.Leu80Pro), were detected in families XF2 and XF3, respectively. These mutations were predicted to be damaging and were not present in the normal controls and existing databases. All three mutations cosegregated with eoHM in each of the three families, in which all heterozygous female members are affected whereas all hemizygous male family members are not affected. Transmission of the mutations and eoHM in the three families demonstrates an unusual pattern of X-linked female-limited inheritance.These data suggest that heterozygous mutations in ARR3 might be responsible for X-linked female-limited eoHM in the three families, a pattern contrary to the standard X-linked recessive trait. To our knowledge, eoHM is the first human disease associated with mutations in ARR3 and the second X-linked female-limited disease identified thus far. Identification of ARR3 associated with X-linked female-limited trait provides not only additional evidence of this unusual hereditary pattern but also an additional model for investigating the molecular mechanism responsible for female-limited phenotypes.

Project description:BackgroundEndotracheal intubation by direct laryngoscopy is a mainstay of advanced airway management performed both in the prehospital environment and in the Emergency Department. Many factors may affect the quality of view during direct laryngoscopy, one of them being the visual acuity (VA) of the intubator under these demanding conditions. While some individual variation in VA is to be expected in younger populations, VA naturally deteriorates in older populations particularly beyond the age of 40 years. This study aimed to describe VA in a younger (n=19) and an older (≥40 years of age, n=20) cohort of intubators at baseline and during simulated adult laryngoscopy, and to compare VA between these two age cohorts.MethodsA baseline near VA test was done using a Sloan Early Treatment Diabetic Retinopathy Study (EDTRS) near vision chart at 40 cm under ambient indoor light. Participants in both age cohorts were then requested to perform laryngoscopy using an airway simulator at 40 cm viewing distance and again at a viewing distance of their choice. Both binocular and monocular VA were tested using a near VA chart placed anterior to the vocal cords of the airway trainer. VA was quantified using the logarithm of the minimum angle of resolution (logMAR). Differences in VA between age cohorts were assessed using independent samples t-tests and differences within age cohorts were assessed using paired samples t-tests.ResultsBinocular and monocular near VA was significantly reduced in the older cohort compared to the younger cohort at baseline (both eyes -0.129 logMAR; p = 0.04, right eye -0.147 logMAR; p = 0.005, left eye -0.197 logMAR; p = 0.002). Within each age cohort VA was significantly reduced during laryngoscopy at a fixed viewing distance (younger; both eyes -0.111 logMAR; p < 0.001, right eye -0.095 logMAR; p < 0.001, left eye -0.105 logMAR; p < 0.001; older; both eyes -0,08 logMAR; p < 0.001, right eye -0.110 logMAR; p < 0.001, left eye -0.065 logMAR; p = 0.01) but this was improved by reducing viewing distance.ConclusionIncreased age was associated with a significant reduction in VA at baseline and during laryngoscopy, which can be partially compensated for by adjusting viewing distance. Although it is currently unknown to what extent this age-related reduction of VA might negatively affect time to place an endotracheal tube or success of placement under direct vision, older intubators should be aware of this effect and consider specialized corrective eyewear in order to maintain an adequate level of VA.

Dataset Information

Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity.

Publications

Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity.

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