Age-Related Macular Degeneration – AMD
Age-related macular degeneration (AMD) is characterized by pathologicalchanges of the retinal pigment epithelium (RPE), progressive degeneration ofphotoreceptors, thickened Bruch’s membrane and choroidal neovascularization.
These alterations lead to the loss of sharp, central vision. It is an age-related
process and usually develops after a person reaches 50 years.
In Western Europe and USA 30% of people older than 75 years suffer from different
types of AMD. 85-90% cases of AMD are dry AMD, which have no treatment.
10-15% cases of AMD are wet AMD, which have number of treatments available(injection into the eye to stop further development) and early diagnosis can savevision.
AMD increased risk assessment enables prevention and early diagnosis of thedisease. The early diagnosis is vital to delay progression of disease and vision loss.
Indications for genetic testing:
1.
2.
3.

Risk determination of at-risk individuals for early diagnosis and prediction of
disease progression
Risk assessment of individuals with family history of AMD
Genetic counseling

AniridiaAniridia is characterized by complete or partial absence of the iris. The symptomsof the disease may include foveal hypoplasia, reduced visual acuity, nystagmus,
photophobia, glaucoma, cataract, and optic nerve hypoplasia.
Aniridia can be isolated or as a part of the WAGR (Wilms tumor, aniridia, genital
anomalies and mental retardation) syndrome.
The prevalence of aniridia is estimated between 1:50 000-1:100 000.
Isolated aniridia is caused by mutations in the PAX6 gene or deletion of aregulatory region controlling PAX6 expression. WAGR syndrome is caused by adeletion of chromosome 11p13, the region harboring the PAX6 and WT1 genes.
Isolated aniridia and WAGR syndrome are inherited in an autosomal
dominant manner.
Indications for genetic testing:
1.
2.
3.

Confirmation of clinical diagnosis
Genetic counseling
Prenatal diagnosis for known familial mutation

Autosomal Dominant Optic Atrophy – ADOA
Autosomal dominant optic atrophy (ADOA) is characterized by progressive
bilateral blindness due to the loss of retinal ganglion cells and optic nerve
deterioration. The severity of vision loss varies from nearly normal vision tocomplete blindness. The age of onset is usually between 4 and 6 years, but ADOA
rarely causes severe vision impairment in childhood.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Genetic counseling
3. Prenatal diagnosis for known familial mutation

Autosomal Dominant Retinitis Pigmentosa
Retinitis pigmentosa is an inherited retinal dystrophy caused by the loss ofphotoreceptors and characterized by retinal pigment deposits visible on fundus
examination. Affected individuals first experience night blindness, followed by
reduction of the peripheral visual field and, sometimes, loss of central vision late in
the course of the disease which eventually leads to blindness after several
decades. Signs and symptoms often first appear in childhood, but severe visualproblems do not usually develop until early adulthood. In some cases, RP ischaracterized by cone-rod dystrophy, in which the decrease in visual acuity
predominates over loss of the visual field. RP is usually nonsyndromic but there arealso many syndromic forms. The main risk factor is a family history of retinitis
pigmentosa.
Indications for genetic testing:
1.
2.
3.
4.

Confirmation of clinical diagnosis
Testing of individuals in subsequent generations with family history ofautosomal dominant retinitis pigmentosa
Genetic counseling
Prenatal diagnosis for known familial mutation

Autosomal Recessive Retinitis Pigmentosa –AR RPRetinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss ofphotoreceptors and characterized by retinal pigment deposits visible on fundus
examination. Affected individuals first experience night blindness, followed by
reduction of the peripheral visual field and, sometimes, loss of central vision late in
the course of the disease which eventually leads to blindness after several
decades. Signs and symptoms often first appear in childhood, but severe visualproblems do not usually develop until early adulthood. In some cases, RP ischaracterized by cone-rod dystrophy, in which the decrease in visual acuity
predominates over loss of the visual field. RP is usually non-syndromic but there
are also many syndromic forms. The main risk factor is a family history of retinitis
pigmentosa.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Bardet Biedl Syndrome, McKusick-Kaufman
Syndrome, Borjeson-Forssman-Lehmann
Syndrome, Alström Syndrome, Albright
Hereditary Osteodystrophy
McKusick-Kaufman Syndrome is characterized by postaxial polydactyly,
congenital heart disease and hydrometrocolpos in females and genital
malformations (hypospadias, cryptorchidism, chordee) in males. Hydrometrocolpos
develops in the female fetus as a result of accumulation of secretions in the vagina
and uterus due to a congenital obstruction. McKusick-Kaufman Syndrome (MKKS)
is inherited in an autosomal recessive manner. MKS is concentrated in the Amish
population, where it affects an estimated 1 in 10,000 people. The disease is caused
by mutations in MKKS (BBS6) gene, which encodes a protein with similarity tomembers of the chaperonin family. Some mutations in MKKS gene are associatedwith McKusick-Kaufman Syndrome, most mutations cause one of the forms ofBardet-Biedl Syndrome (BBS). There are also several symptoms of MKS thatoverlap significantly with BBS.
Bardet-Biedl Syndrome is characterized by male hypogenitalism, complex female
genitourinary malformations, postaxial polydactyly, cone-rod dystrophy, obesity,
cognitive impairment, and renal abnormalities. Renal abnormalities are major causeof morbidity and mortality. The first symbol of retinal degeneration is night
blindness, which later evolves into a progressive loss of peripheral vision. Patientswith Bardet-Biedl also experience central vision loss during childhood oradolescence. Bardet-Biedl Syndrome is inherited in an autosomal recessive
manner. BBS prevalence in Europe is estimated at between 1/125,000 and
1/175,000. BBS is associated with mutations in 18 different genes, that encode
proteins involved in the development and function of primary cilia.
This phenotypic overlap between McKusick-Kaufman Syndrome and Bardet-Biedl
Syndrome in infancy may lead to diagnostic errors, and all children who have been
diagnosed with McKusick-Kaufman Syndrome in infancy should be reevaluated forretinitis pigmentosa and other signs of Bardet-Biedl Syndrome in later childhood.
Borjeson-Forssman-Lehmann Syndrome is characterised by the association of
intellectual deficit with endocrine anomalies, epilepsy, hypogonadism and facial
dysmorphism. The main clinical features evolve with age and show considerable
variation both within and between families. Newborns have small genitalia andlarge ears and many infants have generalized hypotonia. Developmental delay isusually evident before the first birthday; the eventual degree of mental handicap ismild to moderate. Truncal obesity emerges in late childhood and gynaecomastia inadolescence. In late adolescence and adult life, the classically described heavy
facial appearance emerges. Frequent visual problems have also been associatedwith syndrome. The pattern of inheritance is X linked. Borjeson-Forssman-Lehmann
Syndrome is caused by mutations in the PHF6 gene. The differential diagnosis ofobesity related syndromes includes the Prader-Willi, Bardet-Biedl, or Wilson-Turner
Syndromes.
Alström Syndrome is characterized by cone-rod dystrophy, obesity, progressive
sensorineural hearing impairment, dilated cardiomyopathy, the insulin resistancesyndrome, developmental delay and progressive hepatic and renal dysfunction.
The cone-rod retinal dystrophy usually develops within a few weeks after birth, thefirst symptoms are nystagmus and extreme photodysphoria or light sensitivity. It is
progressive and leads to blindness, usually by the second decade of life.
Progressive sensorineural hearing loss presents in the first decade in as many as
70% of individuals. Males may have hypogonadotrophic hypogonadism. Obesity,
insulin resistance and hyperinsulinemia are early and consistent features.
In contrast to BBS, Alström Syndrome is characterized by relative preservation of
cognitive function and the absence of polydactyly. Approximately 450 cases of
Alström Syndrome have been identified worldwide. Alström Syndrome is caused bymutations in the gene ALMS1 and is inherited in an autosomal recessive manner.
Differential diagnosis includes Bardet-Biedl Syndrome, Biemond II Syndrome,
Wolfram Syndrome, Cohen Syndrome, sporadic infantile dilated cardiomyopathy,
and mitochondrial disorders.
Albright Hereditary Osteodystrophy (AHO) is characterised by a wide range offeatures including short stature in adulthood, a tendency for obesity andbrachydactyly (shortening of the bones in the hands and feet). Other features may
include a rounded face, wide neck and small subcutaneous ossifications (hardlumps under the skin). Mental retardation was less frequently described. There aredifferent types of AHO. These are AHO with Pseudo Hypoparathyroidism (PHP) andAHO with Pseudo Pseudo Hypoparathyroidism (PPHP).

PHP is associated with resistance to parathyroid hormone (PTH) and to otherhormones (thyroid-stimulation hormone – TSH, in particular). PHP1a ischaracterized by AHO features, hypoparathyroid manifestations (hypocalcemia,
hyperphosphoremia), elevated PTH levels and decreased erythrocyte Gs activity.
Individuals with PHP-1b have PTH resistance and normal levels of erythrocyte Gs
activity. Classically, patients do not have features of AHO. PHP Ic is characterizedby PTH resistance, generalized hormone resistance, features of AHO and normal
Gs activity.
Patients with pseudopseudohypoparathyroidism (PPHP) have physical findings of
AHO with Gs deficiency but without hormone resistance.
Condition characterized by AHO features and decreased Gs activity is caused byheterozygous inactivating mutations of the GNAS gene. GNAS encodes the alphasubunit of the stimulatory G protein (Gs). Resistance to hormones is determined by
the parental origin of the mutation, a functional maternal GNAS allele has a
predominant role in preventing hormone resistance.
PHP with AHO features is inherited in an autosomal dominant manner.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation
Choroideremia is an X-linked recessive chorioretinal dystrophy that mainly affects
males. Symptoms evolve from night blindness to peripheral visual field loss,
eventually leading to all sight loss by middle age. The vision loss is caused bydegeneration of the retinal pigment epithelium, choriocapillaris, and thephotoreceptor of the eye. Carrier females are generally asymptomatic, small areasof chorioretinal atrophy can be observed with fundus examination. These changes
may cause night blindness and visual field loss after the second decade.
The prevalence of choroideremia is estimated between 1:50 000-1:100 000.
Choroideremia is caused by mutations in the CHM gene, mutation spectrum
includes deletions, duplications, translocations, insertions, nonsense, splice-site,
frameshift and missense mutations.

Cone-Rod Dystrophy
Cone-rod dystrophy (CRD) is an inherited progressive disease characterized by
the loss of the cone and rod photoreceptor cells, responsible for both central andcolor vision. The prevalence of CRD is estimated at 1 in 40,000.
The symptoms of CRD include decreased visual acuity followed by loss of
peripheral vision, loss of color vision, sensitivity to bright lights and decreased
sensitivity in the central visual field.
The pattern of inheritance might be autosomal dominant, autosomal recessive andX-linked inheritance.

Leber Congenital Amaurosis – LCA
Leber congenital amaurosis (LCA) is an early-onset and severe retinal dystrophy
leading to congenital blindness. It is diagnosed by a severely reduced or absent
electroretinogram (ERG) before one year of age. Shortly after birth, patients usually
manifest poor fixation, nystagmus, photophobia, and amaurotic pupils. Later, inmost patients, a large variety of retinal changes appear, including salt-and-pepper
pigmentation, attenuated vessels, and atrophy of the retinal pigment epithelium(RPE). LCA is mostly inherited as an autosomal recessive disorder.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Prediction of disease progression
3. Carrier testing for at-risk family members
4. Genetic counseling
5. Prenatal diagnosis for known familial mutation

Leber Congenital Amaurosis – LCA
Leber congenital amaurosis (LCA) is an early-onset and severe retinal dystrophy
leading to congenital blindness. It is diagnosed by a severely reduced or absent
electroretinogram (ERG) before one year of age. Shortly after birth, patients usually
manifest poor fixation, nystagmus, photophobia, and amaurotic pupils. Later, inmost patients, a large variety of retinal changes appear, including salt-and-pepper
pigmentation, attenuated vessels, and atrophy of the retinal pigment epithelium(RPE). LCA is mostly inherited as an autosomal recessive disorder.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Prediction of disease progression
3. Carrier testing for at-risk family members
4. Genetic counseling
5. Prenatal diagnosis for known familial mutation

Oculocutaneous Albinism, Ocular Albinism,
Hermansky-Pudlak Syndrome, ChediakHigashi Syndrome
Albinism is a group of congenital disorders of melanin production characterized byvariable hypopigmentation and vision defects, including impaired visual acuity,
nystagmus, strabismus, astigmatism, and photophobia. The complete or partial
absence of pigment may affect the eyes, skin and hair (oculocutaneous albinism)or only the eyes (ocular albinism).
Additionally, there are also syndromic forms of albinism such as HermanskyPudlak syndrome andChediak-Higashi syndrome.
The prevalence of all known forms of albinism is estimated to be 1:17 000
newborns.
Oculocutaneous albinism (OCA) is divided into seven types, which are caused bymutations in the respective genes: OCA1 (TYR), OCA2 (OCA2), OCA3 (TYRP1),
OCA4 (SLC45A2), OCA5 (chromosome 4q24), OCA6 (SLC24A5), and OCA7
(C10orf11). All forms of OCA are inherited autosomal recessively.
Ocular albinism is caused by mutations in the GPR143 gene and is inherited in an
X-linked manner.
Mutations in HPS1 (HPS1), AP3B1 (HPS2), HPS3 (HPS3), HPS4 (HPS4), HPS5
(HPS5), HPS6 (HPS6), DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6(HPS9) genes are known to cause different types of Hermansky-Pudlak
syndrome (HPS). HPS is inherited in an autosomal recessive manner andcharacterized by OCA, bleeding disorders, pulmonary fibrosis, and granulomatous
colitis.
The LYST gene is know to be associated with Chediak-Higashi syndrome (CHS).
CHS is inherited in an autosomal recessive manner and characterized by partial
OCA, immunodeficiency, peripheral neuropathy, and bleeding tendency.
Indications for genetic testing:Stargardt Disease
Autosomal recessive Stargardt disease is a juvenile-onset macular dystrophy associated with rapid central
visual impairment, progressive bilateral atrophy of the foveal retinal pigment epithelium, and the frequentappearance of yellowish flecks around the macula and/or in the central and near-peripheral areas of theretina.

Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Vitelliform Macular Dystrophy – VMD
Vitelliform macular dystrophy is an autosomal dominant disorder associated witha vitelliform “egg yolk” lesion that results from abnormal accumulation of lipofuscin
in the retinal pigment epithelium (RPE). Lesions are usually bilateral, but can beunilateral. In the early stages, accumulation of lipofuscin-like material in the RPE isobserved but acuity remains excellent. Later, the affected area becomes deeply
and irregularly pigmented, and as the disorder is progressive, it eventually leads tovision loss. Some cases exhibit multiple extramacular lesions, hemorrhaging, or
macular holes. Vitelliform macular dystrophy generally reveals itself in childhood orsometimes later during the teenage years. Severity of vision loss and age of onset
exhibit inter- and intra-familial variability.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Genetic counseling
3. Prenatal diagnosis for known familial mutation

X-Linked Retinitis Pigmentosa – XLRPRetinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss ofphotoreceptors and characterized by retinal pigment deposits visible on fundus
examination. Affected individuals first experience night blindness, followed by
reduction of the peripheral visual field and, sometimes, loss of central vision late in
the course of the disease and eventually leading to blindness after several
decades. Signs and symptoms often first appear in childhood, but severe visualproblems do not usually develop until early adulthood. In some cases, RP ischaracterized by cone-rod dystrophy, in which the decrease in visual acuity
predominates over the visual field loss. RP is usually nonsyndromic but there arealso many syndromic forms. The main risk factor is a family history of retinitis
pigmentosa.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Determination of female carriers
3. Genetic counseling
Genetic testing for x-linked retinitis pigmentosa is preferred in the male patients/
families with nonsyndromic retinitis pigmentosa and with family history of x-linked
retinitis pigmentosa.

X-Linked Retinoschisis
X-linked retinoschisis is characterized by the abnormal schisis (splitting) of
the retina’s neurosensory layers resulting in reduced visual acuity in affected men.
Carrier females generally remain asymptomatic. Usually the condition is diagnosedin the first decade of life. It manifests with poor vision and reading difficulties. Othersymptoms include night blindness, strabismus and nystagmus. In about half of thecases, peripheral vision is also affected in people with X-linked retinoschisis. Visualacuity remains stable until forties or fifties, when a significant deterioration in visualacuity occurs. In severe cases, vitreous hemorrhage and retinal detachment, which
may lead to impaired vision or blindness, can be seen.
The prevalence of X-linked retinoschisis is estimated to range between
1:5,000-1:25,000 males worldwide.
The disease is caused by mutations on the RS1 gene, mutation spectrum reveals
missense, nonsense, and splice site mutations, deletions, and insertions.

Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Exome Sequencing
Exome sequencing includes the sequencing of the protein coding regions andtheir flankingintronic regions in ~20,000 genes of the human genome. The coding
region represents 1-2% of the human genome but contain approximately 85% ofdisease-causing mutations. Exome sequencing can be an efficient tool for clinicians
to confirm patients’ diagnosis of complicated conditions not covered byconventional testing approaches.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Diagnosis of patients with genetic disorders for which diagnostic panels are notavailable
3. Identification of novel genes responsible for diseases
4. Genetic counseling