A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia.

Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.

Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature.

Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.

Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia.

BACKGROUND: Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia. METHODS: This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11). RESULTS: A novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia. CONCLUSION: Mutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene.

Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families.

PURPOSE: Congenital fibrosis of the extraocular muscles type I (CFEOM1), the most common CFEOM worldwide, is characterized by bilateral ptotic hypotropia, an inability to supraduct above the horizontal midline, horizontal strabismus (typically exotropia), and ophthalmoplegia with abnormal synkinesis. This distinct non-syndromic phenotype is considered autosomal dominant and is virtually always from heterozygous missense mutations in kinesin family member 21A (KIF21A). However, there are occasional KIF21A-negative cases, opening the possibility for a recessive cause. The objective of this study is to explore this possibility by assessing CFEOM1 patients exclusively from consanguineous families, who are the most likely to have recessive cause for their phenotype if a recessive cause exists. METHODS: Ophthalmic examination and candidate gene direct sequencing (KIF21A, paired-like homeobox 2A [PHOX2A], tubulin beta-3 [TUBB3]) of CFEOM1 patients from consanguineous families referred for counseling from 2005 to 2010. RESULTS: All 5 probands had classic CFEOM1 as defined above. Three had siblings with CFEOM. None of the probands had mutations in KIF21A, PHOX2A, or TUBB3. CONCLUSIONS: The lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1. Further studies of such families will hopefully uncover the specific locus(loci).

Infantile esotropia could be oligogenic and allelic with Duane retraction syndrome.

PURPOSE: To describe phenotyping and linkage analysis results for available members from a consanguineous nuclear family with hereditary congenital strabismus. METHODS: Both parents and all 12 children underwent clinical examination. Available affected and several unaffected family members had venous blood sampling for DNA extraction and 10K single nucleotide polymorphism (SNP) genotyping (Affymetrix Gene Chip® Human). Multipoint logarithm of the odds (LOD) score calculations were performed assuming an autosomal recessive mode of inheritance with 100% penetrance and disease allele frequency of 0.01%. RESULTS: Three children had non-syndromic large-angle infantile esotropia without significant hyperopia. A fourth child had left esotropic Duane retraction syndrome. A fifth child who had esotropia in the setting of prematurity and childhood poliomyelitis was excluded from the analysis. A sixth child had keratoconus and was excluded. Both parents and the remaining 6 children had no significant orthoptic or ophthalmic findings. Using linkage analysis including the 4 esotropic children, disease loci were mapped to regions on chromosomes 3p26.3-26.2 and 6q24.2-25.1 using multipoint linkage analysis with LOD scores of 3.18 and 3.25 respectively. Linkage to these regions persisted when the esotropic Duane retraction syndrome patient was excluded from the linkage analysis (LOD scores of 2.00 and 2.32, respectively). CONCLUSIONS: Non-syndromic infantile esotropia could be related to susceptibility loci on chromosomal regions 3p26.3-26.2 and 6q24.2-25.1 and may share alleles that underlie Duane retraction syndrome.

Potential linkage of different phenotypic forms of childhood strabismus to a recessive susceptibility locus (16p13.12-p12.3).

PURPOSE: To perform linkage analysis on an inbred family with members who exhibit different phenotypic forms of childhood strabismus. METHODS: Prospective clinical examination and linkage analysis. RESULTS: three of the ten siblings and their cousin each had a different phenotypic form of childhood strabismus: infantile esotropia with convergence excess, esotropia associated with anisometropic amblyopia, unilateral esotropic Duane syndrome, and monocular elevation deficiency. Linkage analysis for the four strabismic individuals, an unaffected sibling, and the unaffected parents identified a single disease locus on chromosome 16p13.12-p12.3 (Ensembl cytogenetic band) with a 2.5 maximum logarithm of odds score. The region is 6 MB in size and comprises 80 genes. DISCUSSION: Linkage analysis in this unique family suggests that childhood strabismus can be recessive and that different phenotypic forms of childhood strabismus can share the same underlying genotype.

Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles.

OBJECTIVE: To document the genotype for familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance. DESIGN: Interventional family study. PARTICIPANTS: Two affected siblings, 3 asymptomatic siblings, and their 2 asymptomatic parents. METHODS: Ophthalmologic examination and candidate gene analysis (KIF21A and PHOX2A from venous blood samples) of the 2 affected siblings and their parents; confirmatory testing for 3 available asymptomatic siblings. MAIN OUTCOME MEASURES: Significant clinical observations and results of gene testing. RESULTS: The 2 affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; 3 underwent venous blood sampling for confirmatory testing. Candidate gene testing of PHOX2A, the gene for recessive CFEOM (CFEOM2), did not reveal mutation in the 2 patients or their parents. Sequencing of KIF21A, the gene for dominant CFEOM (CFEOM1), revealed heterozygous p.R954L in both affected individuals but in not in their parents or 3 asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive. CONCLUSIONS: Parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. Ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. Unlike other reported KIF21A mutations that cause CFEOM1, the p.R954L variant seems to be associated with abnormal pupils. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Bilateral synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu).

OBJECTIVE: To document the phenotype and determine the genotype of a child with synergistic convergence. DESIGN: Interventional case report. PARTICIPANTS: Patient and nuclear family (7 members total). METHODS: Ophthalmologic, neurologic, and radiologic examination of the proband; venous blood sampling for candidate gene testing of the proband; venous blood sampling for confirmatory testing in other family members. MAIN OUTCOME MEASURES: Clinical and radiologic observations in proband and candidate gene results. RESULTS: The proband, a 9-year-old girl, substituted convergence for horizontal gaze (synergistic convergence) since birth. She also had conjugate pendular nystagmus, asynchronous blinking, and high myopia. No family member had ophthalmologic or medical symptoms. Neuroradiologic imaging revealed hindbrain dysplasia and modest scoliosis. Sequencing of ROB03, the gene associated with horizontal gaze palsy and progressive scoliosis, revealed a novel missense mutation (p.Pro771Leu) that altered an evolutionarily conserved amino acid. Screening the family for this mutation confirmed that both parents were carriers and identified 2 sisters as carriers and 2 brothers as noncarriers. CONCLUSIONS: This is the second reported patient with synergistic convergence and the first associated with a documented pathologic genotype. Unlike the previously reported case (which occurred in the setting of the cranial dysinnervation disorder congenital fibrosis of the extraocular muscles), our patient presumably has a supranuclear cause. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Prolonged pursuit by optokinetic drum testing in asymptomatic female carriers of novel FRMD7 splice mutation c.1050 +5 G>A.

OBJECTIVE: To determine the genotype underlying suspected X-linked infantile nystagmus in a family and to correlate genotype with clinical examination in potential female carriers. METHODS: Ophthalmic examination (ophthalmic, orthoptic, optokinetic [OKN] drum, and electrophysiologic when possible) and candidate gene analysis. RESULTS: Two affected brothers had infantile nystagmus with no evidence of associated visual or neurological disease. The symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM) (bilateral hypotropia, exotropia, ptosis, almost complete ophthalmoplegia, and poorly reactive pupils). A sister, the mother, and the maternal grandmother-all 3 of whom were asymptomatic-had delayed corrective saccades (prolonged pursuit) during OKN drum testing.A brother and the father­both of whom were asymptomatic­had unremarkable examination findings [corrected]. A FRMD7 splice variant (c.1050 + 5 G>A) was identified in the 2 affected brothers and in the 3 asymptomatic women only. Allele sharing analysis further confirmed that the aunt's phenotype was not related to the FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known CFEOM genes (KIF21A, PHOX2A, TUBB3). CONCLUSIONS: Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consistent with the concept of infantile nystagmus being an abnormally increased pursuit oscillation. Further studies are required to determine the reproducibility of this potential female carrier sign. Rather than being FRMD7 related, nystagmus in the maternal aunt represented a second disease in this family, likely related to CFEOM. CLINICAL RELEVANCE: Clinicians can use the OKN drum to assess obligate female carriers in a family suspected of having X-linked nystagmus.