Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel FRMD7 Splice Mutation C.1050 ؉5GϾA

Home , Electroretinography, Optokinetic drum

OPHTHALMIC MOLECULAR GENETICS

SECTION EDITOR: JANEY L. WIGGS, MD, PhD Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel FRMD7 Splice Mutation c.1050 ؉5GϾA

Arif O. Khan, MD; Jameela Shinwari, MSc; Latifa Al-Sharif, BSc; Dania S. Khalil, BSc; Nada Al Tassan, PhD

Objective: To determine the genotype underlying sus- was identified in the 2 affected brothers and in the 3 asymp- pected X-linked infantile nystagmus in a family and to tomatic women only. Allele sharing analysis further con- correlate genotype with clinical examination in poten- firmed that the aunt’s phenotype was not related to the tial female carriers. FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known Methods: Ophthalmic examination (ophthalmic, or- CFEOM genes (KIF21A, PHOX2A, TUBB3). thoptic, optokinetic [OKN] drum, and electrophysi- ologic when possible) and candidate gene analysis. Conclusions: Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consis- Results: Two affected brothers had infantile nystagmus tent with the concept of infantile nystagmus being an ab- with no evidence of associated visual or neurological normally increased pursuit oscillation. Further studies disease. The symptomatic maternal aunt had infantile are required to determine the reproducibility of this po- nystagmus in addition to congenital fibrosis of the ex- tential female carrier sign. Rather than being FRMD7 re- traocular muscles (CFEOM) (bilateral hypotropia, exo- lated, nystagmus in the maternal aunt represented a sec- tropia, ptosis, almost complete ophthalmoplegia, and ond disease in this family, likely related to CFEOM. poorly reactive pupils). A sister, the mother, and the maternal grandmother—all 3 of whom were asymptomatic— Clinical Relevance: Clinicians can use the OKN drum had delayed corrective saccades (prolonged pursuit) dur- to assess obligate female carriers in a family suspected ing OKN drum testing. A brother and the father—both of of having X-linked nystagmus. whom were asymptomatic—had unremarkable examination findings. A FRMD7 splice variant (c.1050ϩ5GϾA) Arch Ophthalmol. 2011;129(7):936-940

YSTAGMUS IS AN EYE MOVE- For familial idiopathic infantile nystag- ment control system ab- mus without associated ocular or neuro- normality characterized logical disease, X-linked inheritance is the by rhythmic involuntary most common inheritance pattern.3,4 Since to-and-fro ocular oscilla- mutation in FRMD7 (FERM domain- tions that can occur with or without asso- containing 7; OMIM 300628) was identi- N 1 ciated visual or neurological disease. Al- fied as a cause for X-linked infantile nys- though nystagmus is most accurately tagmus (OMIM 310700) in 2006,5 at least characterized by waveform analysis, such 40 causative mutations have been de- analysis is not readily available to most oph- scribed, although the specific function of thalmologists.2 Clinicians can describe nys- the gene remains unknown.4,6 As is true for tagmus as jerk (with a fast phase and a slow X-linked disease in general, FRMD7- related nystagmus tends to occur in men. Affected women have been reported more Video available online at commonly in pedigrees with nontruncat- Author Affiliations: Division of www.archophthalmol.com ing mutations as opposed to truncating mu- Pediatric Ophthalmology, King tations, possibly owing to a dominant- Khaled Eye Specialist Hospital phase) or pendular (with apparent equal ve- negative effect of the abnormal protein in (Dr Khan); and Department of locity of the to-and-fro movements).1 In jerk Genetics, King Faisal Specialist the former and nonsense-mediated mRNA Hospital and Research Center nystagmus, directionality (right, left, up- decay (and therefore lack of abnormal pro- 3,4 (Drs Khan and Al Tassan, and beat, downbeat) are based on the fast phase, tein product) in the latter. In addition, Mss Shinwari, Al-Sharif, and although it is the slow phase that is con- skewed X-inactivation toward the mutant Khalil), Riyadh, Saudi Arabia. sidered pathological.1 allele can sometimes be observed in af-

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DXS1047 202.1/196 c.8472C > T C/T c.1050 + 5G > A G/A c.1530T > C T/C DXS691 156.5/154.5

II:1 II:2 II:3 II:5 II:6 II:7 II:8

DXS1047 202.1/198.4 c.8472C > T C/C c.1050 + 5G > A G/G c.1530T > C T/T DXS691 156.5/156.5 DXS1047 202.1 DXS1047 198.3/196 c.8472C > T C c.8472C > T C/T c.1050 + 5G > A G c.1050 + 5G > A G/A II:4 II:9 c.1530T > C T c.1530T > C T/C DXS691 154.5 DXS691 156.5/154.5

III:1 III:2 III:3 III:4 III:5

DXS1047 202.1/198.3 196 198.3 196 c.8472C > T C/T T C T c.1050 + 5G > A G/A A G A c.1530T > C T/C C T C DXS691 154.5/154.5 154.5 156.5 154.5

Figure 1. Family pedigree of FRMD7 showing 3 generations and allele-sharing results. The mutant allele is in red, normal alleles are in black. Arrows point to the individuals who participated in this study.

fected women.7-9 To the best of our knowledge, prior stud- sis, exotropia, poorly reactive pupils, and almost com- ies have not assessed asymptomatic female carriers of plete ophthalmoloplegia.11 Congenital fibrosis of the FRMD7 mutation for potential eye movement control sys- extraocular muscles type 3 (OMIM 600638) is an asym- tem abnormalities by tools readily available to clinicians metric variable form of CFEOM that typically does not in- such as the optokinetic (OKN) drum.3,4 As a near target, volve the pupils and can be due to heterozygous muta- the alternating black-and-white strips of the OKN drum tion in TUBB3 (Tubulin beta-3; OMIM 602661)13,14 or stimulate smooth pursuit toward the direction of rotation KIF21A. There are rare reports of patients with CFEOM and a rapid-onset corrective horizontal saccades in the op- with obvious neurological disease15 but none to our knowl- posite direction. There is one prior study10 that assessed edge with documented constant nystagmus.11-15 asymptomatic female FRMD7 mutation carriers for OKN The purpose of this study is (1) to determine the un- abnormality but not by OKN drum testing. That study, derlying genotype for apparent X-linked infantile nys- which assessed OKN using rear projection screens or liq- tagmus in a family with 2 affected brothers and 1 symp- uid crystal display monitors as a stimulus and eye move- tomatic maternal aunt and (2) to correlate the genotype ment waveform analysis as an endpoint, reported that some with clinical examination and clinical OKN drum test- asymptomatic female carriers showed abnormality. ing in potential female carriers. There is higher incidence of strabismus in patients with FRMD7-related nystagmus than the general popula- METHODS tion10; however, the cranial dysinnervation disorder congenital fibrosis of the extraocular muscles (CFEOM) is not associated with FRMD7 mutation, and infantile nystag- CLINICAL EVALUATIONS mus is not associated with CFEOM.11 Congenital fibrosis of the extraocular muscles is a rare form of congenital in- The family of 2 affected male siblings with possible X-linked comitant strabismus caused by orbital dysinnervation.12 infantile nystagmus was invited to participate in this prospec- Congenital fibrosis of the extraocular muscles type 1 tive genetic study, which was approved by our institutional re- (OMIM 135700), due to heterozygous mutation in KIF21A view boards. Family history was significant for similar “shak- (kinesin family member 21A; OMIM 608283), is charac- ing eyes” in a maternal aunt and uncle, one of whom (the aunt) also had large-angle obvious congenital strabismus with lim- terized by bilateral ptosis, exotropia, hypotropia, and al- ited voluntary eye movements since birth. Available family mem- most complete ophthalmoloplegia. Congenital fibrosis of bers (Figure 1) participated after informed consent: the 2 af- the extraocular muscles type 2 (OMIM 602078), due to fected brothers (III:2, III:4), the symptomatic maternal aunt (II: homozygous mutation in PHOX2A (paired-like homeo- 5), the unaffected sister (III:1), an unaffected brother (III:3), box 2a; OMIM 602753), is characterized by bilateral pto- the 2 unaffected parents (II:4, II:9), and the unaffected mater-

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Corrected on July 21, 2011 nal grandmother (I:2). Participants underwent comprehen- cycloplegic refraction were unremarkable. Findings of sive ophthalmic and orthoptic examination by a pediatric oph- electroretinography and visual evoked potentials were thalmologist; the examination included detailed slitlamp within reference limits. Patient III.2 was a 10-year-old examination to exclude signs of albinism and foveal hypopla- ϩ boy with 20/40 visual acuity in either eye. He preferred sia. Visual acuity was measured using a 10-diopter occluder a moderate right face turn, mild left head tilt, and mild over the contralateral eye. Pursuit and saccades were specifi- cally assessed by OKN drum testing (Model 450; Ophthal- chin depression. Moderate amplitude conjugate pendu- medica Ltd, Winchester, England) at near horizontally and ver- lar nystagmus was observable in the forced primary po- tically in both directions. Full-field electroretinography and sition (Video 1; http://www.archophthalmol.com) and visual evoked potentials were performed in the affected broth- other gaze positions without significant change, al- ers and the unaffected mother according to International So- though the preferred head position suggested dampen- ciety for Clinical Electrophysiology of Vision standards.16 ing with that head position. The nystagmus was variable in direction (mostly horizontal, sometimes vertical/ DNA SEQUENCING AND ALLELE SHARING torsional) and frequency (mostly moderately rapid as shown, at times faster). Delayed corrective saccades (pro- DNA from family members and 246 controls was extracted from longed pursuit) were evident during OKN testing (Video 3 mL of whole blood using a Genetra Puregene Blood kit (Quia- 2). Patient III.4 was a 4-year-old boy with 20/40 visual gen Inc, Valencia, California), according to manufacturer con- acuity in either eye and occasional head nodding. He pre- ditions. The coding exons of FRMD7 (RefSeq NM_194277) were ferred a mild left face turn and chin depression. Large amplified in family members (primers and conditions outlined amplitude conjugate pendular nystagmus was observ- in the eTable; http://www.archophthalmol.com). The opening reading frames of KIF21A (RefSeq NM_017641), PHOX2A (RefSeq able in forced primary position and other gaze positions NM_005169), TUBB3 (RefSeq NM_006086), and coding exons without significant change, although the preferred head were amplified in the affected maternal aunt who also had CFEOM position suggested dampening with that head position (patient II.5 in Figure 1) using previously described primers and (Video 3). The nystagmus was moderately rapid and conditions.13,17 mostly in the horizontal plane, although at times it would Polymerase chain reactions were performed in a 25-µL reac- become more rapid and have small vertical/torsional com- tion volume containing 2.5 µL of 10Xreaction buffer (15-mM ponents. Delayed-corrective saccades (prolonged pur- MgCl2,), 0.2-mM deoxyribonucleotide triphosphates, 10-µM suit) were evident by OKN testing. primers,1UofHotStarTaq polymerase (Qiagen, Dusseldorf, Ger- many), and 10 ng of genomic DNA. Cycling parameters were 94°C for 10 minutes, 30 to 35 cycles of 94°C for 45 seconds, an- SYMPTOMATIC MATERNAL AUNT (II.5) nealing at 59°C for 45 seconds, and 72°C for 45 seconds fol- lowed by a final elongation step at 72°C for 10 minutes. Prod- The patient was a 32-year-old woman with 20/60 visual acu- ucts were visualized on GelStar (Lonza, Maine)–stained agarose ity in the right eye and 20/30 in the left eye. Findings of gels. Polymerase chain reaction products from all exons of FRMD7, ophthalmic examination were significant for low-am- KIF21A, PHOX2A, and TUBB3 were sequenced using an ABI Prism plitude, high-frequency variable (pendular/jerk, vertical/ Big Dye Terminator v3.1 Cycle Sequencing Kit (Applied Biosys- torsional) constant nystagmus, bilateral ptosis, large- tems, Carlsbad, California), as described by the manufacturer. angle exotropia, bilateral hypotropia, and mid-dilated, Results were exported in one of several formats for visualiza- poorly reactive pupils (Video 4). There was virtually com- tion and sequence was analyzed using SeqMan 6.1 (Lasergene 6 plete ophthalmoloplegia other than the nystagmus. There software package; DNASTAR Inc, Madison, Wisconsin). was no convergence or other aberrant eye movement with Allele sharing was performed using 6-carboxyfluorescein (FAM)–labeled primers for the 2 microsatellite markers DXS1049 attempted upgaze. Small, visually insignificant vacuoles were and DX691 flanking the FRMD7 gene. Results were analyzed present in the lens nucleus of both eyes. Results of intra- using Genetic Profiler 2 software (Amersham Pharmacia Bio- ocular pressure measurement, fundus examination, and cy- tech [GE Health Care Life Science], Piscataway, New Jersey). cloplegic refraction were unremarkable. Electroretinogra- Identified variants were assayed in 246 ethnically matched phy and visual evoked potentials were attempted but aborted controls by automated sequencing. because the patient could not keep her head in a comfort- able position for the examination. RESULTS ASYMPTOMATIC WOMEN (III.1, II.4, I.2) CLINICAL MANIFESTATIONS All 3 asymptomatic women had delayed corrective sac- The pedigree of the family was compatible with X- cades (prolonged pursuit) by OKN testing (Video 5). linked inheritance (Figure 1). There was no history of Other than the OKN abnormality, findings of ophthal- consanguinity, although the spouses were from the same mic evaluation were unremarkable except for that of pa- tribal region. No individual had evidence of neurologic tient I.2, who had an acquired corneal scar following child- or ophthalmic disease other than nystagmus, CFEOM, hood infection in her left eye, with hand-motion visual or delayed-onset reflex saccades. acuity in that eye and a sensory exotropia. None had obvious clinical nystagmus. AFFECTED BROTHERS (III.2, III.4) ASYMPTOMATIC MEN (III.3, II.9) For both brothers, there was no evidence of strabismus or pupillary defect. Findings of slitlamp examination, in- Both asymptomatic men had unremarkable findings on traocular pressure measurement, fundus examination, and examination.

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In FRMD7, an intronic variant c.1050ϩ5GϾA (intron 11) was identified in several family members (Figure 2). Affected brothers (III:2 and III:4) were hemizygous for this variant allele, while the unaffected mother (II:4) and unaffected sister (III:1) were heterozygous carriers. The unaffected father (II:9) and brother (III:3) were hemi- A A A A C A A G T A A A G T T T zygous for the normal allele. This variant was absent in the symptomatic aunt (II:5) and it was not present in any B of the 246 controls. Both affected brothers and the 3 asymptomatic female carriers for this variant had abnormalities in results of OKN testing, as documented. In silico analysis predicts that this splice variant would affect the splice donor site, resulting in a 345-base inclusion of intron 11, a resultant frame shift, and a truncated protein of 372 amino acids (rather than 714 amino acids).18,19 This A A A A C A A G T A A G G T T T variant was not found in Human Gene Mutation Data- base Professional version on November 14, 2009.6 In ad- C dition, consensus nucleotide frequency patterns strongly support the expected pathogenicity of the variant’s GϾA ϩ5 intronic change.20(p244) The previously reported nonpathogenic FRMD7 vari- Ͼ Ͼ ants, c.842C T (S281L, rs5977625) and c.1533 t C A A A A C A A G T A A R G T T T (I511, rs5977623), were also identified in family members (Figure 1). Figure 2. Variants of the c.1050ϩ5GϾA mutation identified in FRMD7, showing the sequence chromatogram of a mutant hemizygous (A), a normal ALLELE SHARING ANALYSIS FOR FRMD7 wild type homozygous (B) and a heterozygous carrier (C). Arrows point to the site of mutation. Allele sharing was traced in family members using 2 microsatellite markers flanking FRMD7 gene and the 3 vari- drum sign can easily be tested for by practicing clini- ants identified in this gene in family members. Results con- cians; however, it is unclear how frequently this poten- firmed that only asymptomatic women with oculomotor tial female carrier sign is clinically observable in fami- carrier signs by OKN drum testing and the brothers with lies with X-linked nystagmus. Although the literature infantile nystagmus shared the allele that is in linkage with suggests that the penetrance of clinical signs in women the c.1050ϩ5GϾA mutation. The symptomatic aunt (II:5) with FRMD7 mutation is 64% in nontruncating muta- did not share this allele, confirming that her phenotype is tions and 31.9% in truncating mutations,3 prior studies not related to the FRMD7 mutation (Figure 1). did not assess asymptomatic carrier women for oculomotor abnormality by OKN drum testing. In the one prior CFEOM ANALYSIS IN PATIENT II:5 article that addressed the subject of OKN testing of asymptomatic female carriers, testing was done using screen 10 No pathogenic variants were found in KIF21A, PHOX2A, stimuli and eye movement recording analysis. The au- or TUBB3 in patient II:5. thors described poor OKN gain in a subset of 14 asymptomatic obligate female carriers who were tested. How- ever, because OKN gain abnormalities identified by eye COMMENT movement recording were on a continuum with normal OKN gain values, the authors could not quantify how The OKN drum testing showed prolonged pursuit in many of the 14 had abnormal values; they stated that some asymptomatic female relatives (patients III.1, II.4, I.2) who had abnormal values, while others did not.10 In addi- harbored the splice FRMD7 variant associated with in- tion, the type of FRMD7 mutations were not provided fantile nystagmus in 2 brothers (patients III:2, III:4). This for these 14 individuals.10 Our study reports clinical OKN clinical finding was a female carrier sign for X-linked nys- abnormality and the associated FRMD7 variant for 3 tagmus in the family. The OKN drum is an easily acces- asymptomatic female carriers; however, we are limited sible tool for practicing clinicians and may be useful in by the inclusion of only 3 such individuals. assessing similar families suspected of having X-linked Although the pathophysiology of FRMD7 mutation in nystagmus. infantile nystagmus syndrome remains to be elucidated, A major mechanistic theory of infantile nystagmus is the gene’s FERM domain suggests involvement in sig- that it represents abnormally increased oscillation of the nal transduction between cellular plasma membrane and pursuit system.21 This theory is consistent with our ob- cytoskeleton.22,23 Recent evidence suggests that FRMD7 servation of prolonged pursuit during OKN testing of the plays an important role in the regulation of neurite out- asymptomatic female FRMD7 mutation carriers. The OKN growth and specification22 and that FRMD7 mutation can

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Corrected on July 21, 2011 affect neurite length and neuron branching.5 In situ hy- ter and Gaddah Al-Asali, COA, from the Research De- bridization applied to human embryonic brain tissue at partment of King Khaled Eye Specialist Hospital for their day 56 after ovulation reveals FRMD7 expression in the help. ventricular layer of the forebrain, midbrain, cerebellar pri- mordium, spinal cord, and developing neural retina.5 At day 37, expression was restricted to the midbrain and REFERENCES hindbrain, regions known to be involved in motor control of eye movement.5 Murine models have shown an 1. Hertle RW. Nystagmus in infancy and childhood. Semin Ophthalmol. 2008;23(5): frmd7 expression pattern that mirrors the pattern of genes 307-317. 2. Hamed LM. 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Correction

Error in Abstract. In the Ophthalmic Molecular Genet- ics article titled “Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel FRMD7 Splice Mutation c.1050 ϩ5GϾA” by Khan et al, published in the July issue of the Archives (2011; 129[7]:936-940), there is an error in the “Results” section of the abstract. The sentence, “A brother and the father—all 3 of whom were asymptomatic—had unremarkable examination findings” should have read, “A brother and the father—both of whom were asymptomatic—had unremarkable examination findings.” This article was corrected online.

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