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Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus

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Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus James E. Self, BM, MRCOphth; Fatima Shawkat, PhD; Crispin T. Malpas, BM, MRCOphth; N. Simon Thomas, PhD; Christopher M. Harris, PhD; Peter R. Hodgkins, FRCOphth; Xiaoli Chen, BSc; Dorothy Trump, MD, FRCP; Andrew J. Lotery, MD, FRCOphth Objectives: To perform a genotype-phenotype corre- onstrated no clear causal link between skewing and vari- lation study in an X-linked congenital idiopathic nystag- able penetrance. mus pedigree (pedigree 1) and to assess the allelic vari- ance of the FRMD7 gene in congenital idiopathic Conclusions: We confirm profound phenotypic varia- nystagmus. tion in X-linked congenital idiopathic nystagmus pedi- grees. We demonstrate that other congenital nystagmus Methods: Subjects from pedigree 1 underwent de- genes exist besides FRMD7. We show that the role of X tailed clinical examination including nystagmology. inactivation in variable penetrance is unclear in congen- Screening of FRMD7 was undertaken in pedigree 1 and ital idiopathic nystagmus. in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence Clinical Relevance: We demonstrate that phenotypic changes. X-inactivation studies were performed in variation of nystagmus occurs in families with FRMD7 pedigree 1. mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystag- Results: The nystagmus phenotype was extremely vari- mus, the diagnostic yield is low. X-inactivation assays are able in pedigree 1. We identified 2 FRMD7 mutations. unhelpful as a test for carrier status for this disease. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies dem- Arch Ophthalmol. 2007;125(9):1255-1263 YSTAGMUS IS A DISORDER these pedigrees had causative FRMD7 mu- of oculomotor control tations. An additional 14 small pedigrees and can occur as an iso- with congenital idiopathic nystagmus and Author Affiliations: Clinical lated inherited trait, a an inheritance pattern consistent with X Neurosciences Division, congenital idiopathic linkage were screened and FRMD7 muta- University of Southampton Nnystagmus, or as secondary to other vi- tions were found in 8 of the pedigrees (Drs Self and Lotery and sual (sensory deficit nystagmus) or neu- (57%). Forty-two simplex cases were Ms Chen), and Southampton rological (neurological nystagmus) dis- screened for mutations in this gene and Eye Unit, Southampton General eases.1 In all cases, the underlying yielded 3 mutations (7%). Therefore, the Hospital (Drs Self, Shawkat, pathophysiology is poorly understood. overall contribution of FRMD7 mutations Malpas, Hodgkins, and Lotery), Furthermore, it is unclear which charac- to the cause of both X-linked and single- Southampton, England; Wessex Regional Genetics Laboratory, teristics of the nystagmus phenotype, if ton cases remains relatively unexplored. Salisbury District Hospital, any, are reliable as a diagnostic tool to help In X-linked congenital idiopathic nys- Salisbury, England identify underlying etiology. tagmus pedigrees, penetrance among fe- (Dr Thomas); SensoriMotor Congenital idiopathic nystagmus is ge- male obligate carriers has been vari- Laboratory, Centre for netically heterogeneous and has been de- able,3-5,7 ranging from 30% to 100%. Theoretical and Computational scribed as an autosomal dominant,2 auto- Possible mechanisms for this variability in- Neuroscience, University of somal recessive,3 X-linked dominant,3 or clude skewed X inactivation, genetic modi- Plymouth, Plymouth, England X-linked recessive4 trait. X-linked loci have fiers (such as polymorphisms within in- (Dr Harris); and Academic Unit been identified at Xp11.4-p11.34 and Xq26- teracting proteins), and other nongenetic of Medical Genetics, School of q27.3,5 In November 2006, Tarpey et al6 influences (such as environment) on ocu- Medicine and Centre for Molecular Medicine, Faculty of identified 22 nystagmus-causing muta- lomotor development. These factors may Medical and Human Sciences, tions in the FERM domain–containing 7 also explain why X-linked dominant and University of Manchester, (FRMD7) gene, which resides within the recessive pedigrees, with nystagmus or Manchester, England Xq26-q27 interval. Sixteen X-linked fami- other ocular diseases, can both show link- (Dr Trump). lies underwent linkage analysis and 15 of age to the same region.5,8,9 (REPRINTED) ARCH OPHTHALMOL / VOL 125 (NO. 9), SEP 2007 WWW.ARCHOPHTHALMOL.COM 1255 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 I:1 I:2 II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 III:9 III:10 III:11 III:12 III:13 III:14 III:15 III:16 III:17 III:18 III:19 III:20 IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 IV:9 IV:10 IV:11 IV:12 IV:13 IV:14 IV:15 IV:16 IV:17 IV:18 IV:19 IV:20 IV:21 IV:22 IV:23 IV:24 IV:25 Underwent detailed phenotyping Unaffected male Affected male Unaffected female Affected female Obligate female carrier V:1 V:2 V:3 V:4 V:5 V:6 V:7 V:8 V:9 V:10 V:11 Figure 1. X-linked congenital idiopathic nystagmus pedigree (pedigree 1). This family has 9 affected males, 2 affected females, and 11 obligate female carriers. This article describes high-resolution phenotyping electrophysiological examination but without detailed eye move- using infrared limbal tracking, electrophysiology, and ment recordings. clinical examination in affected and unaffected mem- International Society for Clinical Electrophysiology of Vision– bers of a single large congenital nystagmus pedigree (pedi- standardized electroretinogram (http://www.iscev.org/) and vi- sual evoked potential tests were completed in 2 affected males gree 1) (Figure 1). The role of FRMD7 mutations in 9 and 2 obligate female carriers. Monocular stimulation and a other X-linked families and 28 simplex cases is investi- 3-channel transoccipital electrode montage were employed for gated and, in addition, studies of X inactivation are per- visual evoked potential recordings to optimize detection of neu- formed to investigate the hypothesis that skewing of X ronal misrouting suggestive of ocular albinism. Informed con- inactivation may be a major contributor to the variable sent was obtained from all subjects for genetic studies, and ge- penetrance seen in X-linked nystagmus pedigrees. nomic DNA was isolated from either blood or Oragene saliva sample kits (DNA Genotek Inc, Ottawa, Ontario, Canada). METHODS GENOTYPING AND The study had the approval of the local and regional ethics LINKAGE ANALYSIS committees and conformed to the tenets of the Declaration of Helsinki. Twenty-nine individuals (7 affected males, 2 af- We had previously shown by conventional linkage mapping techniques that the nystagmus gene in pedigree 1 links to an fected females, 11 obligate female carriers, and 9 unaffected 5 members) in a single congenital idiopathic nystagmus pedi- 8-cM region at Xq24-q26.3. This contains the FRMD7 gene, gree underwent detailed clinical examination (Figure 1), in- which is now known to be a cause of X-linked nystagmus and cluding tests for logarithm of the minimum angle of resolu- was thus investigated in this family. DNA was amplified using tion visual acuity, refraction, color vision, intraocular standard polymerase chain reaction (PCR) protocols. Primers pressure; anterior and posterior segment slitlamp examina- for FRMD7 (complementary DNA sequence NM_194277) were designed to include all 12 exons, splice sites, and both the 5Ј tion, including iris transillumination testing in a darkened Ј room; and orthoptic assessment. Twenty-four of these pa- and 3 untranslated regions in amplimers with fewer than 250 tients had detailed recordings of their nystagmus waveform base pairs (primers available on request). Pedigrees 2 through performed using Skalar IRIS IR Light Eye Tracker equipment 10 were not large enough to provide linkage information in- (Cambridge Research Systems Ltd, Rochester, England). dividually, and to avoid errors in light of known X-linked con- Twenty-four eye movement recordings were completed for genital idiopathic nystagmus locus heterogeneity, these fami- each patient. Binocular and uniocular saccades were recorded lies were not combined. Therefore, linkage information was not to calibrate amplitude measurements at ±10° and ±20° from ascertained for these families and definitive proof of X linkage fixation in the horizontal plain using a 1° red square target was not possible. moving at 500-millisecond intervals. Binocular and uniocular optokinetic nystagmus (OKN) measurements were carried SINGLE-STRAND CONFORMATIONAL out to rightward and leftward drifting gratings measuring 0.2 POLYMORPHISM ANALYSIS cycles per degree at a velocity of 25° per second. Waveforms were analyzed while viewed in 5 positions (primary, 10° right, Single-strand conformational polymorphism (SSCP) was per- 10° left, 20° right, and 20° left of fixation), both binocularly formed using standard techniques.10 Specifically, polyacryl- and uniocularly using a 1° red square target. amide gels with glycerol, 6%, were run for 3.5 hours at 25 W An additional 9 congenital idiopathic nystagmus pedigrees per gel at room temperature. We screened for sequence varia- with inheritance consistent with X linkage were identified tions in 96 female controls (182 control X chromosomes), fol- (Figure 2). These pedigrees had similarly detailed clinical and lowed by 2 affected subjects from the first pedigree, 9 pro- (REPRINTED) ARCH OPHTHALMOL / VOL 125 (NO. 9), SEP 2007 WWW.ARCHOPHTHALMOL.COM 1256 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Pedigree 2 Pedigree 3 Pedigree 4 Pedigree 5 Pedigree 6 Pedigree 7 Pedigree 8 Affected male Unaffected male Affected female Unaffected female Obligate female carrier Pedigree 9 Pedigree 10 Figure 2. Nine additional pedigrees screened for FRMD7 mutations. bands from other X-linked nystagmus pedigrees, and 28 cuts at the promoter site on the active (unmethylated) but not nystagmus simplex cases.
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