Asper Biogene – genetic testing company

Lecithin Cholesterol Acyltransferase Deficiency
Sequencing of the LCAT gene

Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Testing of at-risk family members
3. Genetic counseling

Lecithin cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder with prevalence below 1:1,000,000. Mutations in both alleles of LCAT gene result in two autosomal recessive forms of LCAT deficiency, familial LCAT deficiency (FLD), and fish eye disease (FED). Patients with LCAT have extremely low plasma levels of HDL cholesterol; plasma LDL cholesterol and triglyceride levels are widely variable. Many manifestations of the disorder, including corneal opacities, anemia, and renal disease may be developed by early adulthood.

Patients with FLD suffer from a complete lack of LCAT activity, whereas patients with FED have a partial reduction in LCAT activity.

The role of LCAT in the pathogenesis of atherosclerosis has been controversial based on the current research. Considering the low HDL cholesterol levels and often increased triglyceride levels, it is expected that carriers of LCAT mutations would be at increased risk for developing cardiovascular disease. However, many patients do not show a clearly increased risk for developing clinically apparent disease.

References:
Carlson LA and Philipson B. 1979. Fish-eye disease. A new familial condition with massive corneal opacities and dyslipoproteinæmia. Lancet. 2: 922–924.
Kunnen S and Van Eck M 2012. Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis? J Lipid Res. 2012 Sep; 53(9): 1783–1799. doi: 10.1194/jlr.R024513
Saeedi et al 2015. A Review on Lecithin:cholesterol Acyltransferase Deficiency. Clin Biochem 2015 May;48(7-8):472-5. doi: 10.1016/j.clinbiochem.2014.08.014.Epub 2014 Aug 27.
Santamarina-Fojo S et al 2001. Lecithin cholesterol acyltransferase deficiency and fish eye disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited diseases. New York: McGraw-Hill; 2001. p. 2817–33.
Shamburek RDet al 2016 Familial Lecithin:cholesterol Acyltransferase Deficiency: First-in-human Treatment With Enzyme Replacement. J Clin Lipidol Mar-Apr 2016;10(2):356-67. doi: 10.1016/j.jacl.2015.12.007. Epub 2015 Dec 23.

Hyperlipoproteinemia, type 5
Sequencing of the APOA5 gene

Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Testing at risk family members
3. Characteristic findings such as xanthomas
4. Genetic counseling

Hyperlipoproteinemia, type 5 (HLP5) is accompanied by an increase in VLDV (very low density lipoproteins) as well as chylomicrons and a decrease in LDL (low density lipoprotein) and HDL (high density lipoprotein) in the plasma after a fast. HLP5 includes a wide range of pathological conditions having both congenital and acquired aspects and exhibiting moderate to marked hypertriglyceridemia. Features include abdominal pain and eruptive xanthoma. Hyperlipidemia is frequently complicated by pancreatitis.

HLP5 can be caused by mutations in the APOA5 gene. The disease is inherited in an autosomal dominant or an autosomal recessive manner.

References:

Fredrickson DS et al 1966. Familial hyperlipoproteinemia. The Metabolic Basis of Inherited Disease. (2nd ed.) New York: McGraw-Hill (pub.) 1966.
Gotoda T et al 2012. Diagnosis and Management of Type I and Type V Hyperlipoproteinemia. Journal of Atherosclerosis and Thrombosis. 2012;19(1):1-12. doi: 10.5551/jat.10702. Epub 2011 Dec 1.

Familial Lipoprotein Lipase Deficiency
Sequencing of the LPL gene

Deletion/duplication analysis of the LPL gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Differential diagnosis
3. Carrier testing for at-risk relatives
4. Genetic counseling

Familial lipoprotein lipase (LPL) deficiency is characterized by very severe hypertriglyceridemia with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Symptoms of the disease typically develop in childhood.

Familial LPL deficiency is inherited in an autosomal recessive manner. Mutations in the LPL gene cause the disease.

The prevalence of familial LPL deficiency is approximately one in 1,000,000 worldwide.

References:
Burnett JR et al 1999. Familial Lipoprotein Lipase Deficiency. GeneReviews®. Last Update: June 22, 2017.
Viljoen A, Wierzbicki AS. Diagnosis and treatment of severe hypertriglyceridemia. Expert Rev Cardiovasc Ther. 2012;10:505–14.

Apolipoprotein C-II Deficiency
Sequencing of the APOC2 gene

Indications for genetic testing:

1. Differential diagnosis
2. Predictive testing
3. Risk assessment of relatives
4. Genetic counseling

Apolipoprotein C-II (APOC2) deficiency is a rare autosomal recessive disorder with hypertriglyceridemia resulting from impaired activation of lipoprotein lipase. Patients show severe hypertriglyceridemia and chylomicronemia and often manifest xanthomas, lipemia retinalis and pancreatitis. Hypertriglyceridemia is also an important risk factor for development of cardiovascular disease.

In most cases of APOC2 deficiency, causative mutations have been found in the protein-coding region of APOC2 gene.

References:

Takase S et al. Apolipoprotein C-II deficiency with no rare variant in the APOC2 gene. J Atheroscler Thromb. 2013;20(5):481-93. Epub 2013 Mar 7.
Watts GF et al. Demystifying the management of hypertriglyceridaemia. Nat. Rev. Cardiol. 10, 648-661. doi:10.1038/nrcardio.2013.140
Wei CF et al. The structure of the human apolipoprotein C-II gene. Electron microscopic analysis of RNA:DNA hybrids, complete nucleotide sequence, and identification of 5’ homologous sequences among apolipoprotein genes. J Biol Chem, 1985; 260: 15211-15221

Androgen Insensitivity Syndrome
Sequencing of the AR gene

Deletion/duplication analysis of the AR gene

Beta Thalassemia
Sequencing of the HBB gene

Deletion/duplication analysis of the HBB gene

Papillorenal Syndrome
Sequencing of the PAX2 gene

Retinoblastoma
Sequencing of the RB1 gene

Deletion/duplication analysis of the RB1 gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Testing of at-risk family members of an affected individual
4. Genetic counseling
5. Prenatal diagnosis for known familial mutation

Retinoblastoma is a malignant tumor of the developing retina that affects children, usually before the age of 5. The most common sign of retinoblastoma is a white pupillary reflex (leukocoria). Other symptoms may include strabismus, change in eye appearance, reduced visual acuity. Retinoblastoma may be unifocal or multifocal. About 60% of affected individuals have unilateral retinoblastoma, about 40% have bilateral retinoblastoma.

Hereditary retinoblastoma is inherited in an autosomal dominant pattern. Individuals with heritable retinoblastoma have a higher risk of developing non-ocular tumors.

The estimated incidence of retinoblastoma is 1 in 15 000 – 20 000 live births.

References:

Lohmann DR and Gallie BL. Retinoblastoma. GeneReviews® 2000 July 18 (Updated 2015 November 19)
Genetics Home Reference https://ghr.nlm.nih.gov.
Seregard S, et al. Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. Ophthalmology. 2004;111:1228–32.

Pendred Syndrome
Sequencing of the SLC26A4 gene

Deletion/duplication analysis of the SLC26A4 gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Carrier status detection of known mutation
3. Genetic counseling

Pendred syndrome is an autosomal recessive condition characterized by bilateral sensorineural hearing impairment, vestibular and cochlear abnormalities, temporal bone abnormalities and goiter. Considerable phenotypic variability is found even within the same family. Sensorineural hearing loss is usually congenital, severe to profound and non-progressive. However, hearing loss may be later onset and progressive in some patients.

Pendred syndrome, as well as nonsyndromic hearing loss and deafness (DFNB4) show similar phenotypic spectrum. DFNB4 is characterized by nonsyndromic sensorineural hearing loss, vestibular dysfunction, enlarged vestibular aqueduct but normal thyroid function.

For further information:

Alasti F et al. Pendred Syndrome/DFNB4. GeneReviews® 1998 Sept 28 (Updated 2014 May 29)
Napiontek U et al. Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene. J Clin Endocrinol Metab. 2004;89:5347–51.
Reardon W, Trembath RC: Pendred syndrome. J Med Genet 1996; 33: 1037–40.
Stinckens C et al. Fluctuant, progressive hearing loss associated with Menière like vertigo in three patients with the Pendred syndrome. Int J Pediatr Otorhinolaryngol. 2001;61:207–15.

Wilson Disease
Sequencing of the ATP7B gene

Deletion/duplication analysis of the ATP7B gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling

Wilson disease (WD) is an autosomal recessive inherited disorder characterized by the toxic accumulation of copper in various organs including the liver, the cornea and the brain, causing damage therein. The disorder usually manifests in the second decade of life and the hepatic form usually appears earlier than the neurological form. Wilson disease is caused by mutations in the ATP7B gene.

Aniridia
Sequencing of the PAX6 gene

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Genetic counseling
3. Prenatal diagnosis for known familial mutation

Aniridia is characterized by complete or partial absence of the iris. The symptoms of 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 a regulatory region controlling PAX6 expression. WAGR syndrome is caused by a deletion of chromosome 11p13, the region harboring the PAX6 and WT1 genes. Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner.

X-Linked Retinoschisis
Sequencing of the RS1 gene

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

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 diagnosed in 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 the cases, peripheral vision is also affected in people with X-linked retinoschisis. Visual acuity remains stable until forties or fifties, when a significant deterioration in visual acuity 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.

Choroideremia
Sequencing of the CHM gene

Deletion/duplication analysis

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 by degeneration of the retinal pigment epithelium, choriocapillaris, and the photoreceptor of the eye. Carrier females are generally asymptomatic, small areas of 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.

MUTYH-associated Polyposis
Sequencing of the MUTYH gene

Targeted mutation analysis

Del/dup analysis

Indications for genetic testing:

1. 1. Testing of individuals with clinical symptoms similar to FAP or AFAP but in whom no APC gene mutation has been identified
   2. Testing of first degree relatives of the affected individuals
   3. Genetic counseling

MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterized by a variable number of colorectal adenomas with a high risk of developing colorectal cancer. MAP is caused by biallelic germline mutations in MUTYH gene, but there is also evidence that monoallelic mutation carriers have an increased risk for developing colorectal cancer. The clinical symptoms of MAP are often undistinguishable from that of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP) caused by mutations in adenomatous polyposis coli (APC) gene, but the age of onset is usually later compared to FAP patients. The two most common mutations in Caucasians, accounting for about 80% of mutant MUTYH alleles, are p.Y179C and p.G396D (also known as Y165C and G382D).

Familial Hypocalciuric Hypercalcemia
Sequencing of the CASR gene

Deletion/duplication analysis of the CASR gene