.:OrigoGEN:. Diseases

This low-prevalence disease is characterized by non-progressive night blindness and, it is caused by mutations in RDH5, a gene expressed in the retinal pigment epithelium.

OrigoGEN offers the complete sequencing of the RDH5 coding regions.

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Fundus Flavimaculatus

This is one of the retinal pathologies caused by mutations in ABCA4, a gene also responsible for some forms of the Stargardt’s disease, Retinitis Pigmentosa or cone-rod dystrophy. ABCA4 is a paradigm of allelic heterogeneity, as different mutations cause retinal pathologies showing a range of severity and progression. Fundus Flavimaculatus is similar to the Stargardt’s disease, although with a later age-onset.

ABCA4 is a very long gene and sequencing all he coding regions demands considerable time-cost efforts. Around 500 reported mutations cover approximately 60% of the pathogenic alleles (depending on the population) and there are microarray-based techniques that allow the detection of specific mutant alleles. Current estimations consider that around 2% of the population carry recessive mutations in this gene.

OrigoGEN offers the analysis and detection of the reported ABCA4 mutations.

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Glaucoma

Glaucoma is a severe and incapacitating eye disease that affects around 2 to 5% of the population over 50 years. Although complex in ethiology, it is becoming increasingly evident that the genetic component is relevant to the disease, particularly to the primary congenital and the open-angle glaucoma.

Up to now, several loci have been reported to cause glaucoma, but very few causative genes have been identified. Early genetic detection of presymptomatic carriers is crucial to prevent the pathology as the disease is amenable to effective therapy before the optic nerve is irreversibly damaged.

OrigoGEN has designed a molecular diagnostic approach to identify the pathogenic mutations in the main glaucoma-causing genes.

Depending on the clinical diagnosis, OrigoGEN offers the complete sequencing of the coding regions of the most relevant candidate genes (MYOC, OPTN, CYP1B1, WDR36).

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Goldmann-Favre disease (Enhanced S cone syndrome)

This autosomal recessive pathology is characterized by early-onset night blindness and hypersensitivity to blue light. These traits are due to an increased number of S cones -usually the more unfrequent type of photoreceptors-, which confer sensitivity to blue light at the expense of the other cone subpopulations. Mutations in the NR2E3 gene are responsible for this disease.

OrigoGEN offers the complete sequencing of the NR2E3 coding regions.

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Leber Congenital Amaurosis - adLCA, arLCA

Leber Congenital Amaurosis (LCA), the most prevalent form of retinal dystrophy in infants, is a monogenic disease that shows an autosomal dominant or autosomal recessive pattern of inheritance. Thirteen LCA genes have been reported up to now, but others remain to be identified. As in other retinal dystrophies, the mode of inheritance of LCA genes depends more on the mutation than the gene per se. Moreover, some LCA genes are also responsible for other retinal dystrophies, such as Retinitis Pigmentosa.

OrigoGEN has designed a high-throughput strategy to analyze all the reported LCA and RP genes. Our DNAchip is based on SNP (single nucleotide polymorphisms) genotyping of all the candidate genes. This indirect diagnosis requires the genetic analysis of several family members and only in excepcional cases a single patient can be diagnosed.

The many advantages of a family study is that it allows the identification of:
i) the pathogenic gene in the patient;
ii) asymptomatic carriers of the same genetic defect, who may pass it on their descendants;
iii) the healthy family members who are not carriers of the identified genetic defect.
The complete service includes the genetic diagnosis of all the family members who submit their sample at the begining of the analysis.

Prior to the formal request for this type of genetic diagnosis, OrigoGEN will study the pedigree of the family and advise on the more adequate approach, provide instructions for sample preparation, inform about the total costs and the time needed to complete the service.

List of the genes responsible for autosomal dominant and recessive LCA (adLCA and arLCA) included in the OrigoGEN service (13 genes)

AIPL1, CEP290, CRB1, CRX, GUCY2D, IMPDH1, LCA5, LRAT, RD3, RDH12, RPE65, RPGRIP1, TULP1

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Norrie’s disease

This low-prelavent disease is caused by mutations in the NDP gene, which is located in the X chromosome. Around 50% of the male patients bearing mutations in NDP also show mental retardation. Notably, some females carrying mutations in NDP in heterozygosis show the clinical symptoms of the disease.

OrigoGEN offers the complete sequencing of the NDP coding regions.

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Pattern macular dystrophies (adult-onset vitelliform dystrophy and butterfly-shaped dystrophy)

Periferin (RDS) is the major causative gene for both adult-onset vitelliform and butterfly-shaped macular dystrophies. There is a second locus involved in the butterfly-shaped dystrophy for which no pathogenic gene has been identified. Besides, there are some vitelliform dystrophies caused by point mutations in the BEST1 gene.

OrigoGEN offers the complete sequencing of the RDS coding regions.

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Retinitis Pigmentosa: autosomal forms

One of the most relevant contributions of OrigoGEN is the family diagnosis of Retinitis Pigmentosa, the most prevalent cause of blindness in adults (1:3000). Our knowledge on the molecular bases of this disease has allowed us to design an original strategy for the indirect genetic diagnosis based on high-throughput techonologies.

The autosomal Retinitis Pigmentosa (RP) forms can be inherited as a dominant or recessive trait, as it is also the case with Leber Congenital Amaurosis (LCA), a more aggressive but similar retinal dystrophy. RP is a monogenic disorder highly heterogeneous at the clinical and genetic level. Up to now, more than 36 RP genes have been reported but, probably, as many remain to be identiffied. As in other retinal dystrophies, different mutations in a particular gene can be inherited following a dominant or recessive pattern. Moreover, several RP genes are also known to cause other retinal pathologies, such as LCA.

OrigoGEN has designed a DNAchip to genotype a set of SNPs (single nucleotide polymorphisms) for all the RP and LCA candidate genes. This indirect diagnosis requires the genetic analysis of several family members and only in excepcional cases a single patient can be diagnosed.

The many advantages of a family study is that it allows the identification of:
i) the pathogenic gene in the patient;
ii) asymptomatic carriers of the same genetic defect, who may pass it on their descendants;
iii) the healthy family members who are not carriers of the mutant allele.
The complete service includes the genetic diagnosis of all the family members who submit their sample at the begining of the analysis.

Prior to the formal request for this type of genetic diagnosis, OrigoGEN will study the pedigree of the family and advise on the more adequate analysis, provide instructions for sample preparation, and inform about the total costs and the estimated time to complete the service.

List of the genes responsible for autosomal RP in included in the OrigoGEN DNAchip
RP autosomal dominant – adRP (16 genes)
CA4, CRX, FSCN2, GUCA1B, IMPDH1, NR2E3, NRL, PRPF3, PRPF8, PRPF31, RDS, RHO, ROM1, RP1, RP9, SEMA4A

RP autosomal recessive – arRP (20 genes)
ABCA4, CERKL, CNGA1, CNGB1, CRB1, LRAT, MERTK, NR2E3, NRL, PDE6A, PDE6B, PRCD, RGR, RHO, RLBP1, RP1, RPE65, SAG, TULP1, USH2A

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Retinosis Punctata Albescens

This low-prevalence type of retinitis is mainly caused by mutations in the RLBP1 gene.

OrigoGEN offers the complete sequencing of the RLBP1 coding regions.

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Sorsby’s pseudoinflammatory dystrophy

This autosomal dominant retinal dystrophy is mainly caused by mutations in the TIMP3 gene. Although relatively unfrequent it shares many clinical traits with Age-Related Macular Dystrophy (ARMD), the most prevalent disease causing blindness in the elderly.

OrigoGEN offers the complete sequencing of the TIMP3 coding regions.

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Stargardt’s disease

Most cases of the Stargardt’s disease are due to mutations in the ABCA4 gene, although there have been few reports of patients bearing mutations in either CNGB3 o ELOVL4. Besides, some ABCA4 mutations cause another retinal dystrophy, similar to the Stargardt’s disease, called Fundus Flavimaculatus. The main difference between these two pathologies is the onset age, while the Stargardt’s disease appears mostly during the first two decades of life, Fundus Flavimaculatus shows a later age of onset.

ABCA4 is a very long gene and sequencing of all the coding regions demands considerable time-cost efforts. Around 500 mutations cover approximately 60% of the pathogenic alleles (depending on the population) and there are microarray-based approaches that allow the detection of reported mutant alleles.

OrigoGEN offers the analysis and detection of the reported ABCA4 mutations.

Price

X-linked Retinitis Pigmentosa

Around 15-20% of the Retinitis Pigmentosa cases show X-linked inheritance (XLRP). Up to now, only two RP genes have been identified on chromosome X: RP2 and RPGR. RP2 accounts for approximately 10-20% of all the X-linked RP cases, while RPGR, which contains a mutational hot-spot named ORF15, is responsible for around 70% of the cases (amounting to a 11% of all RP patients). Around 10-20% of XLRP cases (depending on the population) are still unassigned.

Current estimations suggest that 50% of the male patients are sporadic XLRP cases. Besides, differently from other X-linked pathologies, some heterozygous carrier women can show the clinical RP symptoms, although the severity and progression of the pathology is more variable than in males.

OrigoGEN offers the complete sequencing of all the coding regions of the RP2 and RPGR genes, including exon ORF15.

Prior to the formal request for this type of genetic diagnosis, OrigoGEN will study the pedigree of the family and advise on the more adequate analysis, provide instructions for sample preparation, inform about the total costs and the time needed to complete the service.

Price

X-linked Retinoschisis

This pathology affects mainly patients of the male gender and its prevalence is estimated around 1:15.000- a 1:30.000. It is caused by mutations in the RS1 gene, which is located in the X chromosome.

OrigoGEN offers the complete sequencing of the RS1 coding regions.

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