Norrie Disease: NDP Gene Deletion/Duplication

NDP-related retinopathies are X-linked recessive disorders characterized by very early childhood eye diseases/disorders due to degenerative and proliferative changes of the neuroretina. The spectrum of retinal findings ranges from Norrie disease (ND) to X-linked familial exudative vitreoretinopathy (FEVR), including some cases of persistent hyperplastic primary vitreous (PHPV), Coats disease, and advanced retinopathy of prematurity (ROP). These phenotypes appear to be a continuum of retinal findings with considerable overlap. The ocular findings that permit a presumptive diagnosis of an NDP-related retinopathy include the following:

     Bilateral, often symmetric, involvement of the eyes

     Normal-sized eyes, with normal anterior chambers and usually clear lenses at birth

     Vitreous abnormalities (hemorrhage, membranes, detachment, and/or vitreoretinal attachments)

     Presence of fibrous and vascular retinal changes at birth with progressive changes through childhood or adolescence

The most severe phenotype is Norrie disease (ND). Retinal findings include greyish-yellow fibrovascular masses (pseudogliomas), which appear in the first few months of life and result in total blindness. Approximately 50% of individuals with ND show some form of progressive mental disorder, often with psychotic features, and about one-third of patients develop sensorineural deafness in the second decade. In addition, some individuals have more complex phenotypes, including growth failure and seizures.

Less severe phenotypes include: persistent hyperplastic primary vitreous (PHPV), characterized by a fibrotic white stalk from the optic disk to the lens; X-linked familial exudative vitreoretinopathy (XL-FEVR), characterized by peripheral retinal vascular anomalies with or without fibrotic changes; retinopathy of prematurity (ROP); and Coats disease, an exudative proliferative vasculopathy. Phenotypes can vary within families.

The diagnosis of NDP-related retinopathies relies upon a combination of clinical findings and molecular genetic testing of NDP (Xp11.4), the only gene known to be associated with NDP-related retinopathies. Sequence analysis identifies disease-causing mutations in about 85% of affected males. Approximately 15% of mutations are deletions involving all or part of the NDP gene. Males with NDP deletions appear to exhibit a more severe phenotype than those with non-deletion mutations. In addition to the ocular manifestations of ND, affected individuals with a deletion may also have microcephaly, severe-to-profound mental retardation, seizures, myoclonus, somatic growth failure, and/or delayed puberty.

Rarely, a partial or mild ocular phenotype occurs in carrier females, presumably secondary to non-random X-chromosome inactivation. The majority of mothers of a male proband are carriers of an NDP disease-causing mutation, even when the family history is negative. Rarely, affected males have a de novo mutation. Women who are carriers may have a germline mutation or may have inherited the mutant gene.

For patients with a suspected NDP-related retinopathy, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

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This test is indicated for:

• Confirmation of a clinical diagnosis of an NDP-related retinopathy in individuals who have tested negative for sequence analysis
• Carrier testing in adult females with a family history of an NDP-related retinopathy who have tested negative for sequence analysis

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

• Sequencing analysis of the NDP gene is available (YL) and is required before deletion/duplication analysis.
• ACGH array-based test for deletion/duplication analysis of 64 differentX-linked intellectual disability genes is available (OL).
• Prenataltesting is available to adult females who are confirmed carriers ofmutations. Please contact the laboratory genetic counselor to discussappropriate testing prior to collecting a prenatal specimen.

Requisition Forms

• Comprehensive Molecular Test Requisition Form
• Eye Disorders/Hearing Loss/Ciliopathies Test Requisition Form

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