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).

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.

Clinical heterogeneity of PLA2G6-related Parkinsonism: analysis of two Saudi families.

BACKGROUND: Recessive mutations in PLA2G6 have been associated with different neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation and more recently, early-onset dystonia parkinsonism. METHOD: Targeted-next generation sequencing using a custom Neurology panel, containing 758 OMIM-listed genes implicated in neurological disorders, was carried out in two index cases from two different Saudi families displaying early-onset levodopa-responsive Parkinsonism with pyramidal signs and additional clinical features. The detected mutations were verified in the index cases and available family members by direct sequencing. RESULTS AND CONCLUSION: We identified a previously described PLA2G6 homozygous p.R741Q mutation in three affected and two asymptomatic individuals from two Saudi families. Our finding reinforces the notion of the broadness of the clinical spectrum of PLA2G6-related neurodegeneration.

Parkinson's Disease in Saudi Patients: A Genetic Study.

Parkinson's disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.

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.

Congential fibrosis of the extraocular muscles type I (CFEOM1) on the Arabian Peninsula.

PURPOSE: To assess for KIF21A mutation in the first two reported Saudi Arabian families with the classic phenotype of congenital fibrosis of the extraocular muscles type I (CFEOM1). METHODS: Clinical examination and genetic testing by amplification refractory mutation system (ARMS) assay for KIF21A R954W, the most common KIF21A mutation worldwide. RESULTS: Clinical examination was consistent with classic CFEOM1 in both Family A and Family B. All participating patients (one child from Family A and four adults from Family B) were heterozygous for KIF21A R954W mutation. CONCLUSIONS: CFEOM1 is rare is Saudi Arabia as it is in the rest of the world. The finding of R954W mutation in the historically isolated population of the Arabian Peninsula confirms that R954 is a "hotspot" for KIF21A mutation.