Publications by authors named "Oscar F Chacon-Camacho"

28 Publications

  • Page 1 of 1

Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability.

Am J Med Genet A 2020 11 9;182(11):2773-2777. Epub 2020 Sep 9.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Hereditary mucoepithelial dysplasia (HMD) is an uncommon autosomal dominant disease affecting skin, mucosae, hair, eyes, and lungs. Prominent clinical features include non-scarring alopecia, mucosal erythema, perineal erythematous intertrigo, and involvement of the conjunctival mucosa. To date, 20 familial or sporadic HMD cases have been described, most of them originating from Caucasian ethnic groups. In this study, a novel HMD pedigree, including an affected father and his daughter, is reported. Clinical expression showed significant differences in affected subjects, especially in the distribution and severity of skin lesions. Exome sequencing demonstrated that both affected subjects carried a heterozygous c.1669C>T (p.Arg557Cys) pathogenic variant in the SREBF1 gene. Our results improve the knowledge of the clinical and genetic features of HMD. In addition, a comparative review of the clinical features of all published HMD cases is presented.
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http://dx.doi.org/10.1002/ajmg.a.61849DOI Listing
November 2020

Newborn transient patterned hyperpigmentation and anophthalmia.

Bol Med Hosp Infant Mex 2020 ;77(3):146-148

Facultad de Medicina y Psicología, Universidad Autónoma de Baja California-Campus Tijuana, Tijuana, Baja California. Mexico.

Background: Transient pigmentary lines of the newborn are uncommon cutaneous lesions of unknown etiology. To date, only a few cases have been described.

Case Report: A patient with a combination of transient pigmentary lines and ocular malformation is described. Molecular analysis of the SRY-box 2 (SOX2) and MIFT genes was conducted to rule out any monogenetic etiology.

Conclusions: Worldwide, this is the eighth case of transient pigmentary lines of the newborn reported, and the first associated with anophthalmia. No mutations in the analyzed genes (SOX2 and MIFT) were identified. Therefore, somatic mutations could be responsible for this anomaly.
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http://dx.doi.org/10.24875/BMHIM.19000191DOI Listing
January 2020

Clinical, histopathological, and in silico pathogenicity analyses in a pedigree with familial amyloidosis of the Finnish type (Meretoja syndrome) caused by a novel gelsolin mutation.

Mol Vis 2020 2;26:345-354. Epub 2020 May 2.

Research Unit, Institute of Ophthalmology "Conde de Valenciana," Mexico City, Mexico.

Purpose: Familial amyloidosis of the Finnish type (FAF) is an inherited amyloidosis arising from mutations in the gelsolin protein (GSN). The disease includes facial paralysis, loose skin, and lattice corneal dystrophy. To date, FAF has been invariably associated with substitution of Asp214 in GSN. We describe the clinical, histopathological, and genetic features of a family with FAF due to a novel GSN mutation.

Methods: Five affected adult individuals in a three-generation FAF pedigree were included in the study. Histopathological analysis was performed on an eyelid skin biopsy from one patient. Genetic analysis included next-generation sequencing (NGS) and Sanger sequencing for confirmation of the variant. Several tools for in silico analysis of pathogenicity for the novel variant and to predict the effect of the amino acid replacement on protein stability were used.

Results: Three older adult affected patients exhibited corneal lattice dystrophy, cutis laxa, and facultative peripheral neuropathy. Two younger adult individuals presented only with corneal amyloid deposits. NGS identified a heterozygous c.1631T>G transversion, predicting a novel p.Met544Arg mutation. All in silico tools indicated that p.Met544Arg is deleterious for GSN functionality or stability.

Conclusions: The results expand the molecular spectrum of GSN-linked systemic amyloidosis. The novel p.Met544Arg pathogenic variant is predicted to affect gelsolin function, presumably by impairing a potential calcium-sensitive, actin-binding region.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195602PMC
May 2020

Previously undescribed phenotypic findings and novel ACTG1 gene pathogenic variants in Baraitser-Winter cerebrofrontofacial syndrome.

Eur J Med Genet 2020 May 3;63(5):103877. Epub 2020 Feb 3.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico; Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico. Electronic address:

Baraitser-Winter cerebrofrontofacial syndrome is an autosomal dominant disease characterized by multiple congenital abnormalities and intellectual disability, which is caused by mutations in either the ACTB or ACTG1 genes. In this report, we described novel phenotypic findings in two Mexican patients with the disorder in whom two novel ACTG1 mutations (c.176A > G, p.Gln59Arg; and c.608C > T, p.Thr203Met) were identified.
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http://dx.doi.org/10.1016/j.ejmg.2020.103877DOI Listing
May 2020

Extracranial midline defects in a patient with craniofrontonasal syndrome with a novel EFNB1 mutation.

Am J Med Genet A 2020 05 5;182(5):1223-1229. Epub 2020 Feb 5.

Center for Registry and Research in Congenital Anomalies (CRIAC), Service of Genetics and Cytogenetic Unit, Pediatric Division, "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara, Guadalajara, Mexico.

We report a female patient with craniofrontonasal syndrome (CFNS) who in addition showed other cranial and extracranial midline defects including partial corpus callosum agenesis, ocular melanocytosis, pigmentary glaucoma, duplex collecting system, uterus didelphys, and septate vagina. She was found to have a novel pathogenic variant in exon 5 of EFNB1, c.646G>T (p.Glu216*) predicted to cause premature protein truncation. From our review, we found at least 39 published CFNS patients with extracranial midline defects, comprising congenital diaphragmatic hernia, congenital heart defects, umbilical hernia, hypospadias, and less frequently, sacrococcygeal teratomas, and internal genital anomalies in females. These findings support that the EFNB1 mutations have systemic consequences disrupting morphogenetic events at the extracranial midline. Though these are not rigorously included as midline defects, we found at least 10 CFNS patients with congenital anomalies of the kidney and urinary tract, all females. Additionally, uterus didelphys and ocular melanocytosis observed in our patient are proposed also as a previously unreported EFNB1-related midline defects. In addition, this case may be useful for considering the intentional search for genitourinary anomalies in future patients with CFNS, which will be helpful to define their frequency in this entity.
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http://dx.doi.org/10.1002/ajmg.a.61506DOI Listing
May 2020

Characterization of novel pathogenic variants causing glutaric aciduria type 1 in the southeast of Mexico.

Mol Genet Metab Rep 2019 Dec 13;21:100533. Epub 2019 Nov 13.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Biallelic mutations of the gene result in Glutaric Aciduria type 1 (GA1; OMIM #231670), an uncommon autosomal recessive inborn error caused by the deficiency of glutaryl-CoA dehydrogenase (CCDH), a mitochondrial matrix protein involved in the degradation of l-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic deficiency leads to the accumulation of neurotoxins causing macrocephaly at birth, hypotonia and dystonia due to bilateral striatal injury, that evolves with aging, if untreated, to fixed dystonia and akinetic-rigid parkinsonism. In this article, we describe the results of molecular studies of 5 unrelated patients with GA1 in Southern Mexico. Mutational analysis identified 2 novel likely pathogenic variants (p.Leu130Pro and p.Gly391Val), 1 pathogenic variant that is predicted to cause a premature stop codon (p.Leu370*), and 2 previously reported pathogenic variants (p.Arg294Trp and p.Arg294Gln). The recurrence of the p.Leu130Pro variant (60% of mutant alleles) suggested a possible founder mutation effect. Our results expand the mutational spectrum in GA1 patients and support the importance of early diagnosis through newborn screening that promotes early nutritional treatment and prevents metabolic crisis.

Take Home Message: Glutaric Aciduria type 1 has a wide mutational spectrum; the p.Leu130Pro variant may be a founder mutation in Southeast Mexico.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879986PMC
December 2019

Extensive genic and allelic heterogeneity underlying inherited retinal dystrophies in Mexican patients molecularly analyzed by next-generation sequencing.

Mol Genet Genomic Med 2020 01 17;8(1). Epub 2019 Nov 17.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Background: Retinal dystrophies (RDs) are one of the most genetically heterogeneous monogenic disorders with ~270 associated loci identified by early 2019. The recent application of next-generation sequencing (NGS) has greatly improved the molecular diagnosis of RD patients. Genetic characterization of RD cohorts from different ethnic groups is justified, as it would improve the knowledge of molecular basis of the disease. Here, we present the results of genetic analysis in a large cohort of 143 unrelated Mexican subjects with a variety of RDs.

Methods: A targeted NGS approach covering 199 RD genes was employed for molecular screening of 143 unrelated patients. In addition to probands, 258 relatives were genotyped by Sanger sequencing for familial segregation of pathogenic variants.

Results: A solving rate of 66% (95/143) was achieved, with evidence of extensive loci (44 genes) and allelic (110 pathogenic variants) heterogeneity. Forty-eight percent of the identified pathogenic variants were novel while ABCA4, CRB1, USH2A, and RPE65 carried the greatest number of alterations. Novel deleterious variants in IDH3B and ARL6 were identified, supporting their involvement in RD. Familial segregation of causal variants allowed the recognition of 124 autosomal or X-linked carriers.

Conclusion: Our results illustrate the utility of NGS for genetic diagnosis of RDs of different populations for a better knowledge of the mutational landscape associated with the disease.
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http://dx.doi.org/10.1002/mgg3.1044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978239PMC
January 2020

Giant Ocular Lipodermoid Cyst in Encephalocraniocutaneous Lipomatosis: Surgical Treatment and Genetic Analysis.

Am J Case Rep 2019 Oct 25;20:1566-1571. Epub 2019 Oct 25.

Department of Cornea and Refractive Surgery, Conde de Valenciana Institute of Ophthalmology, Mexico City, Mexico.

BACKGROUND Encephalocraniocutaneous lipomatosis is a rare neurocutaneous disorder characterized by cutaneous, ocular, and central nervous system anomalies; its molecular etiology was recently identified. This report describes the surgical treatment and genetic characterization of a giant ocular lipodermoid cyst secondary to encephalocraniocutaneous lipomatosis. CASE REPORT An 11-year-old girl with past medical history of absence seizures presented with a reddish protruding mass in her right eye involving the temporal conjunctiva and the peripheral temporal cornea; eyelid closure was not possible due to mass protrusion. She also presented skin tags at the level of the external canthus and 3 alopecic areas at the level of the scalp compatible with nevus psiloliparus. No family history was reported. A dermoid cyst was suspected and excisional biopsy was performed under general anesthesia. A large conjunctival and lamellar corneoscleral resection was done, followed by a corneal tectonic graft. Molecular analysis was carried out, including PCR and Sanger sequencing on DNA obtained from the mass. After surgery, the patient achieved complete eyelid closure, reduction of ocular surface symptoms, and improved aesthetic appearance. Histological analysis confirmed a lipodermoid cyst; genetic tests confirmed a mosaic activating mutation in FGFR1 (c.1638C>A, p.Asn546Lys). The diagnosis was encephalocraniocutaneous lipomatosis. CONCLUSIONS ECCL is a rare condition; an accurate diagnosis comprising clinical and genetic aspects can facilitate the monitoring of possible complications, improve the multidisciplinary treatment, and provide valuable information for future therapy developments. In this case, the patient's quality of life improved significantly, ocular symptoms disappeared, and a good esthetic appearance was achieved.
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http://dx.doi.org/10.12659/AJCR.918684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824416PMC
October 2019

Clinical characterization and identification of five novel FOXL2 pathogenic variants in a cohort of 12 Mexican subjects with the syndrome of blepharophimosis-ptosis-epicanthus inversus.

Gene 2019 Jul 29;706:62-68. Epub 2019 Apr 29.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico; Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico. Electronic address:

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant entity characterized by eyelid malformations and caused by mutations in the forkhead box L2 (FOXL2) gene. Clinical and genetic analyses of large cohorts of BPES patients from different ethnic origins are important for a better characterization of FOXL2 mutational landscape. The purpose of this study is to describe the phenotypic features and the causal FOXL2 variants in a Mexican cohort of BPES patients. A total of 12 individuals with typical facial findings were included. Clinical evaluation included palpebral measurements and levator function assessment. The complete coding sequence of FOXL2 was amplified by PCR and subsequently analyzed by Sanger sequencing. A total of 11 distinct FOXL2 pathogenic variants were identified in our cohort (molecular diagnostic rate of 92%), including 5 novel mutations. Our results broaden the BPES-related mutational spectrum and supports considerable FOXL2 allelic heterogeneity in our population.
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http://dx.doi.org/10.1016/j.gene.2019.04.073DOI Listing
July 2019

Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies.

Mol Genet Genomic Med 2019 05 19;7(5):e625. Epub 2019 Mar 19.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Background: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies.

Methods: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism.

Results: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids.

Conclusion: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.
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http://dx.doi.org/10.1002/mgg3.625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503218PMC
May 2019

Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma.

Am J Med Genet A 2018 12 18;176(12):2710-2719. Epub 2018 Nov 18.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.
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http://dx.doi.org/10.1002/ajmg.a.40644DOI Listing
December 2018

Sclerocornea-Microphthalmia-Aphakia Complex: Description of Two Additional Cases Associated With Novel FOXE3 Mutations and Review of the Literature.

Cornea 2018 Sep;37(9):1178-1181

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana," Mexico City, Mexico.

Purpose: To describe 2 sporadic Mexican patients having congenital bilateral, total sclerocornea, aphakia, and microphthalmia associated with novel mutations in the FOXE3 gene.

Methods: Two affected individuals with congenital bilateral, total sclerocornea, aphakia, and microphthalmia underwent detailed examinations including slit-lamp examination, visual acuity, and intraocular pressure measurements. Ocular ultrasonography and ultrasound biomicroscopy were performed. Genomic DNA was isolated from blood leukocytes in each subject, and molecular analysis of the FOXE3 gene was performed. For cosegregation analysis, presumable pathogenic variants were tested by Sanger sequencing in parental DNA.

Results: Molecular screening of FOXE3 was performed in 2 cases with congenital bilateral, total sclerocornea, aphakia, and microphthalmia. In patient 1, genetic analysis demonstrated a novel homozygous c.291C>G (p.Ile97Met) FOXE3 pathogenic variant. In patient 2, compound heterozygosity for the novel c.387C>G (p.Phe129Leu) transversion and for the previously reported c.244A>G (p.Met82Val) transition, was recognized.

Conclusions: The sclerocornea-microphthalmia-aphakia complex is a severe malformative ocular phenotype resulting from mutations in the FOXE3 transcription factor. To date, patients from at least 14 families with this uncommon ocular disorder have been described. The identification of 2 novel pathogenic variants in our patients expands the mutational spectrum in FOXE3-related congenital eye disorders. In addition, we performed a review of the clinical and genotypic characteristics of all published patients carrying biallelic FOXE3 mutations.
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http://dx.doi.org/10.1097/ICO.0000000000001655DOI Listing
September 2018

Retinal phenotypic characterization of patients with retinopathydue to the homozygous p.Ala1773Val mutation.

Mol Vis 2018 1;24:105-114. Epub 2018 Feb 1.

Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana," Mexico City, Mexico.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in .

Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient.

Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed.

Conclusions: The results indicate that this particular mutation in is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800431PMC
November 2018

The clinical implications of molecular monitoring and analyses of inherited retinal diseases.

Expert Rev Mol Diagn 2017 11 5;17(11):1009-1021. Epub 2017 Oct 5.

a Genetics Department-research Unit , Institute of Ophthalmology 'Conde de Valenciana' , Mexico City , Mexico.

Introduction: Retinal dystrophies (RDs) are the most common cause of inherited blindness and one of the most genetically heterogeneous human diseases. RDs arise from mutations in genes involved in development and function of photoreceptors or other retinal cells. Identification of the genetic defect causing RD allows accurate diagnosis, prognosis, and counseling in affected patients. Molecular diagnosis is a tremendous challenge in RDs due to their locus and phenotypic heterogeneity. As conventional DNA sequencing approaches are impractical in such situation, Next Generation Sequencing (NGS)-based protocols are needed to identify RD-causing mutations. This is being accomplished by sequencing RD gene panels or by whole exome or whole genome sequencing approaches. Areas covered: This review discusses the current strategies for molecular diagnosis in RDs including their advantages and limitations, as well as their utility in diagnosis of non-syndromic versus syndromic RDs. Results of ongoing gene therapy protocols in RDs are also presented. Expert commentary: Molecular diagnosis in RD improves the medical management of patients. Importantly, demand for molecular screening for RDs is greatly expanding not only as a result of increasing development and availability of NGS technologies, but also of the growing number of gene-based clinical trials offering a potential treatment to patients.
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http://dx.doi.org/10.1080/14737159.2017.1384314DOI Listing
November 2017

PAX6 allelic heterogeneity in Mexican congenital aniridia patients: expanding the mutational spectrum with seven novel pathogenic variants.

Clin Exp Ophthalmol 2017 12 15;45(9):875-883. Epub 2017 Jun 15.

Genetics Department, Institute of Ophthalmology 'Conde de Valenciana', Mexico City, Mexico.

Importance: The importance of the study was to describe the clinical characteristics and mutational analysis of Mexican patients with aniridia.

Background: Aniridia is a panocular hereditary eye disease caused by mutations in the PAX6 transcription factor. Mutation detection rate is highly variable ranging from 30% to 90% in different populations. Very few studies have been published about the PAX6 mutational analysis in aniridia patients from Mexico. In order to establish a more representative PAX6 mutational frequency in the country, a cohort of 22 Mexican unrelated aniridia probands were analysed in this study.

Design: Case series.

Participants: A total of 22 Mexican probands with bilateral isolated aniridia and their available relatives were included.

Methods: Sanger sequencing was used for the mutational analysis of all coding exons and flanking intronic regions of PAX6.

Main Outcome Measures: Clinical characteristics and results of PAX6 mutational analysis in probands with aniridia and available family members.

Results: Molecular analysis of PAX6 in 22 index cases with aniridia allowed the identification of a total of 16 different mutations. Seven of these pathogenic variants are novel, including c.183C>G, p.(Y61*); c.718delC, p.(R240Efs*3); c.1149_1152delTCAG, p.(P385Wfs*139); c.257_266delAAATAGCCCA, p.(K86Sfs*35); c.836_843dupGCAACACA p.(P282Afs*86); c.1032+2_1032+3insT; and c.141+2T>A. Inter and intrafamilial phenotypic heterogeneity was found.

Conclusions And Relevance: The mutational diagnostic rate in this series was 77%, which is comparable with reports from other populations. Importantly, no founder mutations were identified in this case series. Our results add 7 novel PAX6 pathogenic variants to the aniridia-related mutational spectrum and reveal considerable PAX6 allelic heterogeneity in this population.
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http://dx.doi.org/10.1111/ceo.12982DOI Listing
December 2017

Novel FREM1 mutations in a patient with MOTA syndrome: Clinical findings, mutation update and review of FREM1-related disorders literature.

Eur J Med Genet 2017 Mar 19;60(3):190-194. Epub 2017 Jan 19.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico; Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico. Electronic address:

Manitoba-oculo-tricho-anal (MOTA) syndrome is an uncommon condition arising from biallelic mutations of FREM1 gene and clinically characterized by a variable spectrum of eyelid malformations, aberrant hairline, bifid or broad nasal tip, and gastrointestinal anomalies. In this report, we describe a patient with a phenotype compatible with MOTA syndrome (aberrant anterior hair line, hypertelorism, unilateral anophthalmia, and bifid and broad nasal tip) in whom two novel FREM1 mutations (c.305 A > G, p.Asp102Gly; and c.2626delG, p.Val876Tyrfs*16) were identified in the compound heterozygous state, thus broadening the mutational spectrum of the disease. We performed a literature review of the clinical and genetic features of individuals carrying FREM1 mutations.
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http://dx.doi.org/10.1016/j.ejmg.2017.01.005DOI Listing
March 2017

Clinical and Genetic Findings in Mexican Patients with Duane Anomaly and Radial Ray Malformations/Okihiro Syndrome.

Rev Invest Clin 2016 Sep-Oct;68(5):269-274

Genetics Department Research Unit, Instituto de Oftalmología Conde de Valenciana, Mexico City, Mexico.

Background: Okihiro syndrome is an autosomal-dominant condition characterized by radial ray malformations associated with Duane anomaly and other clinical characteristics. SALL4 mutations have been identified in 80-90% of patients with Duane- Radial ray defects/Okihiro syndrome. We report the clinical findings and results of SALL4 sequencing from a group of Mexican patients with this disorder.

Objective: Clinical description and identification of SALL4 mutations in Mexican subjects with radial defects and Duane anomaly.

Materials And Methods: Five unrelated index cases were studied. Complete ophthalmologic and general physical examination was performed in all patients. Polymerase chain reaction amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of SALL4 gene were carried out in genomic DNA.

Results: A novel heterozygous deletion was identified in one patient. Intragenic heterozygous single nucleotide polymorphisms on SALL4 gene ruled out deletions of some exons in other affected patients in whom non-pathogenic variants were identified by Sanger sequencing. Likewise, multiplex ligation-dependent probe amplification analysis ruled out large deletions in this gene.

Conclusion: We observed a low frequency of SALL4 mutations in Mexican patients with clinical criteria of Okihiro syndrome.
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July 2017

Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.

Am J Med Genet A 2016 07 3;170(7):1934-7. Epub 2016 May 3.

Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618706PMC
July 2016

Identification and expression analysis of a novel intragenic EFNB1 mutation causing craniofrontonasal syndrome.

Meta Gene 2014 Dec 28;2:25-31. Epub 2013 Nov 28.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico ; Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by mutations in the EFNB1 gene and characterized by distinctive craniofacial and digital malformations. In contrast with most X-linked traits, female patients with CFNS display a more severe phenotype than males. In this report, the clinical, molecular and RNA expression analyses of a female subject with CFNS are described. A novel c.445_449delGAGGG deletion in exon 3 of EFNB1 was demonstrated in this patient. To assess the effect of this novel mutation at the transcript level, the expression of EFNB1 mRNA was studied by quantitative RT-PCR. To our knowledge, this is the first time that an EFNB1 transcript carrying a truncating mutation in exon 3 is demonstrated to undergo degradation by nonsense-mediated mRNA decay. Our results expand the mutational spectrum of CFNS and add to the functional consequences of truncating EFNB1 mutations.
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http://dx.doi.org/10.1016/j.mgene.2013.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287793PMC
December 2014

Acro-spondylo-pubic dysostosis associated with cataracts, microcephaly, and normal intelligence.

Am J Med Genet A 2015 Feb 26;167A(2):282-6. Epub 2014 Nov 26.

Genetics Department-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

We report on an adult male with normal intelligence who exhibited an unusual combination of microcephaly, dysostoses of limbs, vertebrae, patellae, and pubic bone, camptodactyly of all fingers, and syndactyly of toes, absent nails on thumbs and some fingers, bilateral cataract, cryptorchidism, polythelia, and nipple-like skin pigmentations of shoulders and upper back. We have been unable to find a description of a similar combination of manifestations in literature. The cause of the anomalies remains unknown.
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http://dx.doi.org/10.1002/ajmg.a.36851DOI Listing
February 2015

Clinical and genetic characteristics of mexican patients with juvenile presentation of niemann-pick type C disease.

Case Rep Neurol Med 2014 2;2014:785890. Epub 2014 Oct 2.

Department of Medical Genetics, Centro Médico Nacional "20 de Noviembre", ISSSTE, San Lorenzo No. 502E, Colonia del Valle Sur, Del. Benito Juárez, 03100 México, DF, Mexico.

Niemann-Pick type C disease (NPC) is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348∗ and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.
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http://dx.doi.org/10.1155/2014/785890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202276PMC
October 2014

Homozygosity mapping identifies a GALK1 mutation as the cause of autosomal recessive congenital cataracts in 4 adult siblings.

Gene 2014 Jan 7;534(2):218-21. Epub 2013 Nov 7.

Research Unit-Genetics, Institute of Ophthalmology, "Conde de Valenciana", Mexico City, Mexico; Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico. Electronic address:

Objective: Monogenic congenital cataract is one of the most genetically heterogeneous ocular conditions with almost 30 different genes involved in its etiology. In adult patients, genotype-phenotype correlations are troubled by eye surgery during infancy and/or long-term ocular complications. Here, we describe the molecular diagnosis of GALK1 deficiency as the cause of autosomal recessive congenital cataract in a family from Costa Rica.

Methods: Four affected siblings were included in the study. All of them underwent eye surgery during the first decade but medical records were not available. Congenital cataract was diagnosed by report. Molecular analysis included genome wide homozygosity mapping using a 250K SNP Affymetrix microarray followed by PCR amplification and direct nucleotide sequencing of candidate gene.

Results: Genome wide homozygosity mapping revealed a 6Mb region of homozygosity shared by two affected siblings at 17q25. The GALK1 gene was included in this interval and direct sequencing of this gene revealed a homozygous c.1144C>T mutation (p.Q382) in all four affected subjects.

Conclusions: This work demonstrates the utility of homozygosity mapping in the retrospective diagnosis of a family with congenital cataracts in which ocular surgery at early age, the lack of medical records, and the presence of long term eye complications, impeded a clear clinical diagnosis during the initial phases of evaluation.
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http://dx.doi.org/10.1016/j.gene.2013.10.057DOI Listing
January 2014

Exome sequencing identifies RDH12 compound heterozygous mutations in a family with severe retinitis pigmentosa.

Gene 2013 Oct 27;528(2):178-82. Epub 2013 Jul 27.

Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Objective: Retinitis pigmentosa (RP) is the most prevalent type of inherited retinal degeneration and one of the commonest causes of genetically determined visual dysfunction worldwide. To date, approximately 35 genes have been associated with nonsyndromic autosomal recessive RP (arRP), however the small contribution of each gene to the total prevalence of arRP and the lack of a clear genotype-phenotype correlation complicate the genetic analysis in affected patients. Next generation sequencing technologies are powerful and cost-effective methods for detecting causative mutations in both sporadic and familial RP cases.

Methods: A Mexican family with 5 members affected from arRP was studied. All patients underwent a complete ophthalmologic examination. Molecular methods included genome-wide SNP homozygosity mapping, exome sequencing analysis, and Sanger-sequencing confirmation of causal mutations.

Results: No regions of shared homozygosity among affected subjects were identified. Exome sequencing in a single patient allowed the detection of two missense mutations in the RDH12 gene: a c.446T>C transition predicting a novel p.L149P substitution, and a c.295C>A transversion predicting a previously reported p.L99I replacement. Sanger sequencing confirmed that all affected subjects carried both RDH12 mutations.

Conclusions: This study adds to the molecular spectrum of RDH12-related retinopathy and offers an additional example of the power of exome sequencing in the diagnosis of recessively inherited retinal degenerations.
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http://dx.doi.org/10.1016/j.gene.2013.07.021DOI Listing
October 2013

Nasopalpebral lipoma-coloboma syndrome: clinical, radiological, and histopathological description of a novel sporadic case.

Am J Med Genet A 2013 Jun 1;161A(6):1470-4. Epub 2013 May 1.

Department of Genetics, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico.

Nasopalpebral lipoma-coloboma syndrome is an extremely uncommon autosomal dominant condition characterized by congenital upper eyelid and nasopalpebral lipomas, colobomata of upper and lower eyelids, telecanthus, and maxillary hypoplasia. A few familial and sporadic cases of this malformation syndrome have been previously reported. Here, the clinical, radiological, and histopathological features of a sporadic Mexican patient with the nasopalpebral lipoma-coloboma syndrome are described. To our knowledge, this is the first time that craniofacial 3D computed tomography imaging was used for a detailed assessment of the facial lipoma.
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http://dx.doi.org/10.1002/ajmg.a.35916DOI Listing
June 2013

ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation.

Exp Eye Res 2013 Apr 16;109:77-82. Epub 2013 Feb 16.

Department of Genetics-Research Unit, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico.

The aim of this study was to assess the mutational spectrum of the ABCA4 gene in a cohort of patients with Stargardt disease from Mexico, a previously uncharacterized population. Clinical diagnosis in each patient was supported by a complete ophthalmological assessment that included visual acuity measurement, a slit lamp examination, a fundus examination and photography, electroretinography, fluorescein angiography, and computerized visual fields testing. Molecular analysis was performed by PCR amplification and direct nucleotide sequence of the 50 exons of the ABCA4 gene in genomic DNA. A total of 31 unrelated subjects with the disease were enrolled in the study. Molecular analysis in the total group of 62 alleles allowed the identification of 46 mutant ABCA4 alleles carrying 29 different pathogenic disease-associated mutations. Two ABCA4 mutant alleles were detected in 20 of the 31 patients (64.5%), a single disease allele was identified in six (19.4%), and no mutant alleles were detected in five of the cases (16.1%). Most patients with two ABCA4 mutations (11/20, 55%) were compound heterozygotes. Twelve variants were novel ABCA4 mutations. Nucleotide substitutions were the most frequent type of variation, occurring in 26 out of 29 (89.7%) different mutations. The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively. Haplotype analyses of intragenic SNPs in four subjects carrying the p.A1773V mutation supported a common origin for this mutation. In conclusion, this is the first report of ABCA4 molecular screening in Latin American Stargardt disease patients. Our results expand the mutational spectrum of the disease by adding 12 novel ABCA4 pathogenic variants and support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. The identification of recurrent mutations in our cohort will direct future ABCA4 molecular screening in patients from this ethnic group.
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http://dx.doi.org/10.1016/j.exer.2013.02.006DOI Listing
April 2013

Expanding the phenotype of gingival fibromatosis-mental retardation-hypertrichosis (Zimmermann-Laband) syndrome.

Am J Med Genet A 2011 Jul 27;155A(7):1716-20. Epub 2011 May 27.

Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico.

Zimmermann-Laband syndrome (ZLS) is a rare disorder characterized by gingival fibromatosis, hypertrichosis, intellectual disability, and absence and/or hypoplasia of the nails or terminal phalanges of the hands and feet. The syndromic features of ZLS are highly variable and can overlap with other entities featuring gingival fibrosis. This study describes a patient with ZLS with novel findings, including colpocephaly, hemivertebra, polydactyly, hyperpigmentation, and hemihyperplasia. Thus, the present report expands the phenotypic spectrum of this uncommon syndrome.
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http://dx.doi.org/10.1002/ajmg.a.34030DOI Listing
July 2011

OCT findings in young asymptomatic subjects carrying familial BEST1 gene mutations.

Ophthalmic Genet 2011 Mar 15;32(1):24-30. Epub 2010 Nov 15.

Department of Genetics and Research Unit, Institute of Ophthalmology "Conde de Valenciana," Mexico City.

Purpose: Best disease is an autosomal dominant retinal degeneration characterized by the presence of yellow lesions in the macula causing decreased central visual acuity at later stages. Best disease is caused by heterozygous mutations in BEST1, a gene located at chromosome 11q13. In the present study, we describe the clinical and molecular analysis of two multigenerational families with Best disease and correlate the optical coherence tomography (OCT) findings in asymptomatic and symptomatic subjects carrying BEST1 mutations.

Methods: Two Mexican families with 3 affected generations each were studied. Probands underwent full ophthalmologic examination including fundus examination, fluorescent angiography (FAG), and electro-oculogram (EOG). Fourier-domain 3D OCT was performed in a number of symptomatic and asymptomatic subjects from these two pedigrees. PCR amplification and automated nucleotide sequencing of the 11 exons of the BEST1 gene in genomic DNA were also performed.

Results: Eighteen members of family 1 were molecularly tested. Seven subjects, including 4 young asymptomatic patients, carried a W24C heterozygous mutation in BEST1. OCT imaging in a 6-year-old asymptomatic patient carrying this mutation did not demonstrate retinal lesions. Fifteen subjects from family 2 were molecularly tested. Four patients, including 2 asymptomatic subjects, carried a heterozygous Q293K BEST1 mutation. OCT imaging in an asymptomatic 8-year-old individual with the Q293K mutation demonstrated bilateral subfoveal lesions and unilateral serous retinal detachment. Symptomatic patients showed severe retinal lesions by OCT.

Conclusions: Our results add to the clinical, imaging, and molecular knowledge of Best disease and suggest that OCT can recognize retinal lesions in some asymptomatic carriers of BEST1 mutations as early as 8 years of age.
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http://dx.doi.org/10.3109/13816810.2010.524906DOI Listing
March 2011

Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico.

Clin Exp Ophthalmol 2010 Apr;38(3):277-83

Department of Genetics, Institute of Ophthalmology 'Conde de Valenciana', Mexico City, Mexico.

Background: von Hippel-Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p. Up to 60% of VHL patients show ocular involvement with retinal hemangioblastoma being the most common observed lesion. In this study, we describe the clinical and genetic characteristics of two familial and one apparently non-familial case of VHL ascertained at our institution.

Methods: Clinical evaluation included ophthalmologic examination and imaging exams for tumours identification; molecular analysis consisted of PCR amplification of the complete VHL gene coding sequence (three exons) and automated nucleotide sequencing.

Results: A total of eight affected subjects were demonstrated to carry a causative mutation in VHL. Affected subjects from family #1 had a c.245G > C change, predicting a p.R82P substitution, affected individuals from family #2 were shown to have a c.266T > C change, leading to a p.L89P missense substitution, whereas the apparently non-familial case had a c.298-299insA mutation. One subject from family #2 was a non-penetrant carrier. No ocular anomalies were found in two adult affected subjects carrying the p.L89P mutation.

Conclusion: Considerable interfamilial and intrafamilial clinical variability as well as one instance of non penetrance were recorded in these VHL disease cases. Three different mutations were demonstrated, including the c.298-299insA one base insertion, which has been previously described in two unrelated families from our country. Although additional studies are needed, our data suggest that this insertion could be a 'founder' mutation.
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http://dx.doi.org/10.1111/j.1442-9071.2010.02241.xDOI Listing
April 2010