Eye Diseases NGS panel of 294 genes

Fanconi Anemia
NGS panel

Deletion/duplication analysis

Craniosynostosis
NGS panel

Deletion/duplication analysis

Noonan Spectrum Disorders/Rasopathies NGS panel

Deletion/duplication analysis of selected regions

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Parental testing in case of a causative mutation has been identified in an affected  individual
3. Genetic counseling
4. Prenatal diagnosis

Skeletal Dysplasia
NGS panel

Deletion/duplication analysis

Deletion/duplication analysis of selected regions

Age-Related Macular Degeneration
Targeted mutation analysis

Indications for genetic testing:
1. Risk determination of at-risk individuals for early diagnosis and prediction of disease progression
2. Risk assessment of individuals with family history of AMD
3. Genetic counseling

Age-related macular degeneration (AMD) is characterized by pathological changes of the retinal pigment epithelium (RPE), progressive degeneration of photoreceptors, 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 save vision.
AMD increased risk assessment enables prevention and early diagnosis of the disease. The early diagnosis is vital to delay progression of disease and vision loss.

Anophthalmia/Microphthalmia/Coloboma/Anterior Segment Dysgenesis NGS panel

Achromatopsia NGS panel

Thyroid Cancer
NGS panel

Del/dup analysis

Fanconi Anemia
NGS panel

Del/dup analysis

Pulmonary Arterial Hypertension
NGS panel

Deletion/duplication analysis

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

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder caused by cellular proliferation and fibrosis of the small pulmonary arteries, which results in a progressive rise in pulmonary vascular resistance. Initial symptoms include dyspnea, fatigue, syncope, chest pain, palpitations and leg edema. The mean age at diagnosis is 36 years.

Although the pathogenesis of PAH begins in the pulmonary circulation, right heart failure is the major cause of morbidity and mortality.

PAH can be idiopathic (defined by absence of an underlying risk factor), heritable, induced by drugs or toxins, or associated with conditions such as connective tissue disease, congenital heart disease, portal hypertension, HIV infection, or schistosomiasis.

Hereditary PAH is inherited in an autosomal dominant manner. BMPR2 mutations remain the most common genetic cause of PAH, accounting for ~80% of hereditary PAH and ~20% idiopathic PAH. Pathogenic variants in other genes are less common (1%-3%).

References:
Austin ED et al 2002. Heritable Pulmonary Arterial Hypertension. GeneReviews®
Humbert M et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43, 13S–24S (2004).
Simonneau G et al. 2013. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 62, D34–D41 (2013).
Tielemans B et al 2019. TGFβ and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension. Drug Discov Today. 2019 Mar; 24(3):703-716.
Tonelli A R et al.2013. Causes and circumstances of death in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 188, 365–369 (2013).

Neurodegeneration with Brain Iron Accumulation
NGS panel

Deletion/duplication analysis

Epilepsy
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Testing of at risk family members for known mutations
3. Prenatal diagnosis for known familial mutations
4. Genetic counseling

Epilepsy is a clinically and genetically heterogeneous group of disorders characterized by epileptic seizures and other symptoms of neurological problems. Epilepsy can be caused by strokes, brain tumors, head injuries, structural brain abnormalities, brain infections and genetic syndromes.

The epilepsies can be classified into three classes: genetic generalized, focal and encephalopathic epilepsies, with several specific disorders within each class. The genetic generalized epilepsy syndromes include juvenile myoclonic epilepsy and childhood absence epilepsy among others. Focal epilepsy syndromes include temporal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy and autosomal dominant epilepsy with auditory features. Epileptic encephalopathies are severe, early onset conditions characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis.

Epilepsy is often a concurrent condition in individuals with intellectual disability, autism or schizophrenia.

Genetic factors are relevant in the development of epilepsy. Most genes being implicated in epilepsy are involved in dysfunction or dysregulation of ion channels.

References:

Chang BS, Lowenstein DH (2003). “Epilepsy”. N. Engl. J. Med. 349 (13): 1257–66.
Hildebrand MS et al. Recent advances in the molecular genetics of epilepsy. J Med Genet. 2013;50:271–9.
Myers CT and Mefford hC. Advancing epilepsy genetics in the genomic era. Genome Medicine2015 7:91 

Dystonia
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk relatives
3. Prenatal diagnosis for known familial mutation
4. Genetic counseling

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing repetitive movements and/or abnormal postures. Dystonic movements are typically patterned and twisting, affecting the neck, torso, limbs, eyes, face, vocal chords, and/or a combination of these muscle groups. The movements may be associated with tremor.

There are a number of different forms of dystonia, and many diseases are associated with the condition. Dystonia can be classified clinically and/or etiologically by anatomic changes (nervous system pathology) and causation (inherited, acquired, or idiopathic). Classifying dystonia by clinical features includes age of onset, body distribution, temporal pattern, and associated features.

Hereditary dystonias are usually inherited in an autosomal dominant manner and less commonly in an autosomal recessive or X-linked manner.

References:

Albanese A et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013;28:863–73.
Klein C et al. Dystonia Overview. GeneReviews® 2003 Oct 28 (Updated 2014 May 1).
Koc F and Yerdelen D. Metformin-induced paroxysmal dystonia. Neurosciences (Riyadh). 2008 Apr;13(2):194-5.

Parkinson’s Disease
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Determination of differential diagnosis
3. Genetic counseling

Parkinson’s disease (PD) is a progressive neurodegenerative disorder mainly affecting the motor system. PD is characterized by tremor, rigidity, bradykinesia, poor balance, and difficulty with walking. Non-motor findings include insomnia, depression, anxiety, behavioral problems, at a later stage of the disease psychosis and dementia may occur.

PD is most commonly a non-Mendelian disorder resulting from the effects of multiple genes as well as environmental risk factors. Mendelian forms of PD are inherited in an autosomal dominant, autosomal recessive, or, rarely, X-linked manner. The most common sporadic form of PD manifests around age 60, however, young-onset and juvenile-onset are seen.

References:

Davie CA. A review of Parkinson’s disease. 2008. Br. Med. Bull. 86 (1): 109–27.
Farlow J et al. Parkinson Disease Overview. GeneReviews® 2004 May 25 (Updated 2014 Feb 27).

Frontotemporal Dementia
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Determination of differential diagnosis
3. Testing of at-risk asymptomatic adults
4. Genetic counseling

Frontotemporal dementia (FTD) is a degenerative condition characterized by progressive neuronal loss in the temporal and frontal lobes of the brain. Clinical presentations may include behavioral changes, language disturbances, aphasia, extrapyramidal signs, rigidity, bradykinesia, supranuclear palsy, saccadic eye movement disorders, and mutism.

FTD usually occurs between ages 40 and 60 years, but may appear earlier or later. Most individuals diagnosed with the disorder have had an affected parent with the clinical symptoms of frontotemporal dementia. FTD is inherited in an autosomal dominant manner.

References:

Cardarelli R et al. Frontotemporal dementia: a review for primary care physicians. Am Fam Physician. 2010 Dec 1;82(11):1372-7.
Harms MM et al. TARDBP-Related Amyotrophic Lateral Sclerosis. GeneReviews® 2009 April 23 (Updated 2015 March 12).
Hsiung G-YR and Feldman HH. GRN-Related Frontotemporal Dementia. GeneReviews® 2007 Sept 7 (Updated 2013 March 14).
Van Swieten JC et al. MAPT-Related Disorders. GeneReviews® 2000 Nov 7 (Updated 2010 Oct 26).

Hypertrophic Cardiomyopathy
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Determination of differential diagnosis
3. Testing of at-risk family members
4. Genetic counseling

Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of left ventricular hypertrophy (LVH) that is not solely explained by abnormal loading conditions. HCM is a significant cause of sudden cardiac death in competitive athletes. The clinical features of HCM are highly variable ranging from asymptomatic LVH to arrhythmias, to refractory heart failure. The symptoms include shortness of breath, orthostasis, presyncope, syncope, palpitations, and chest pain.

The prevalence in the general population is estimated at 1/500.

HCM is most commonly caused by mutations in one of the genes that encode different components of the sarcomere and is inherited in an autosomal dominant manner. In 3–5% of the cases affected individuals carry two mutations in the same gene (compound heterozygous or homozygous), or in different genes (digenic). This is associated with a more severe phenotype with younger age of onset and more adverse events.

References:

Cirino AL and Ho C. Hypertrophic Cardiomyopathy Overview. GeneReviews®. 2008 August 5 (Updated 2014 Jan 16) 
Elliott PM et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. European Heart Journal (2014) 35, 2733–2779.
Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349:1064–75.
Richard P et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107: 2227–2232.
Richard P et al. Homozygotes for a R869G mutation in the beta-myosin heavy chain gene have a severe form of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 2000; 32: 1575–1583.

Hereditary Spastic Paraplegia NGS panel

Targeted mutation analysis

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Determination of differential diagnosis
3. Carrier status detection of known mutation
4. Prenatal diagnosis for known familial mutation
5. Genetic counseling

Hereditary Spastic Paraplegia (HSP) is a group of clinically and genetically heterogeneous disorders characterized by lower extremity spasticity and weakness.

HSP is classified as uncomplicated, or pure, when only spinal involvement occurs, and is classified as complicated when accompanied by other system involvement or other neurologic findings such as ataxia, seizures, intellectual disability, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy.

HSP can be inherited in an autosomal dominant, autosomal recessive, x-linked recessive or maternally inherited (mitochondrial) manner.

The prevalence of all hereditary spastic paraplegias is estimated to be 2 to 6 in 100,000 people worldwide.

References:

Fink JK. Hereditary Spastic Paraplegia Overview. GeneReviews® 2000 Aug 15 (Updated 2014 Feb 6)
National Institute of Health 2008. Hereditary Spastic Paraplegia Information Page.
Sawhney IM, Bansal SK, Upadhyay PK, et al. Evoked potentials in hereditary spastic paraplegia. Ital J Neurol Sci. 1993 Sep. 14(6):425-8.

Usher Syndrome
NGS panel

Targeted regions sequencing

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

Usher syndrome is a combination of retinitis pigmentosa and sensorineural hearing loss with or without vestibular dysfunction. Usher syndrome represents 50% of all cases with deafness and blindness. Usher syndrome is inherited in an autosomal recessive manner. Three major clinical types can be distinguished. Usher syndrome type I (USH1) is characterized by severe to profound congenital hearing loss, RP and vestibular areflexia. Patients with Usher syndrome type II (USH2) have moderate to severe hearing loss, RP and normal or variable vestibular function. Patients with Usher syndrome type III (USH3) have progressive hearing loss, RP and variable vestibular function.

Waardenburg Syndrome
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

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

Waardenburg syndrome (WS) is a group of genetic conditions characterized by sensorineural hearing loss and pigmentary abnormalities of the iris, hair, and skin, along with dystopia canthorum. Hearing loss is congenital, typically non-progressive, either unilateral or bilateral, and sensorineural.

The classic sign of hair pigmentation anomaly with WS is white forelock appearing typically in the teen years. Ocular pigmentary manifestations may include complete or segmental heterochromia or hypoplastic or brilliant blue irides.

Waardenburg syndrome affects an estimated 1 in 20,000-40,000 people.

Four types of WS can be distinguished by physical characteristics and genetic cause. Types I and III are inherited in an autosomal dominant manner, types II and IV are autosomal recessive.

References:

Farrer LA et al. Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium. Am J Hum Genet. 1992;50:902–13.
Milunsky JM. Waardenburg Syndrome Type I. GeneReviews® 2001 July 30 (Updated 2014 Aug 7)
Shields CL et al. Waardenburg syndrome: iris and choroidal hypopigmentation: findings on anterior and posterior segment imaging. JAMA Ophthalmol. 2013;131:1167–73.
Tamayo ML et al. Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability. Am J Med Genet A. 2008;146A:1026–31.

Treacher Collins Syndrome
NGS panel

Deletion/duplication analysis of the TCOF1 gene

Indications for genetic testing:

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

Treacher Collins syndrome (TCS) is a congenital disorder characterized by craniofacial deformities, external ear abnormalities, and eye anomalies. The most characteristic features of TCS are micrognathia, conductive hearing loss, coloboma of the lower eyelid, and absence of the lower eyelashes. Less common signs include cleft palate and unilateral or bilateral choanal stenosis or atresia.

TCS affects an estimated 1 in 50,000 people. The disorder has an autosomal dominant pattern of inheritance. Approximately 1% of TCS is inherited in an autosomal recessive manner.

References:

Chiara C et al. Novel mutations of TCOF1 gene in European patients with treacher Collins syndrome. 2011. Medical Genetics 12.
Katsanis SH and Jabs EW. Treacher Collins Syndrome. GeneReviews®. 2004 July 20 (Updated 2012 Aug 30)
Trainor PA et al. Treacher Collins syndrome: etiology, pathogenesis and prevention. 2008. European Journal of Human Genetics 17 (3): 275–283.

Stickler Syndrome
NGS panel

Indications for genetic testing:

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

Stickler syndrome is a group of hereditary conditions affecting connective tissue. Stickler syndrome is characterized by ocular findings, distinctive facial abnormalities, hearing loss, skeletal abnormalities, and joint problems.

Eye findings may include high myopia, cataract, vitreoretinal or chorioretinal degeneration, and retinal detachment. Hearing loss can be both conductive and sensorineural. Affected individuals have a characteristic flattened facial appearance caused by midfacial underdevelopment and cleft palate.

Stickler syndrome is inherited in an autosomal dominant or autosomal recessive manner. Stickler syndrome affects approximately 7,500 to 9,000 newborns.

References:

Annunen S et al. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. 1999. Am J Hum Genet 65 (4): 974–83.
Printzlau A, Andersen M. Pierre Robin sequence in Denmark: a retrospective population-based epidemiological study. Cleft Palate Craniofac J. 2004;41:47–52.
Robin NH et al. Stickler Syndrome. GeneReviews® 2000 June 9 (Updated 2014 Nov 26)

Branchiootorenal Syndrome
NGS panel

Deletion/duplication analysis of the EYA1 gene

Indications for genetic testing:

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

Branchiootorenal (BOR) syndrome is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial arch anomalies (branchial clefts, fistulae, cysts), and renal abnormalities. Renal malformations may include urinary tree malformation, renal hypoplasia or agenesis, renal dysplasia, renal cysts. In some cases, end-stage renal disease develops later in life.

BOR manifests wide clinical heterogeneity between affected individuals. Estimated prevalence of the disease is 1/40,000.

BOR syndrome is transmitted in an autosomal dominant manner.

References:

Fraser FC et al. Genetic aspects of the BOR syndrome—branchial fistulas, ear pits, hearing loss and renal anomalie. Am J Med Genet1978; 2: 241–252
Melnick M et al. Branchio‐oto‐renal dysplasia and branchio‐oto dysplasia: two distinct autosomal dominant disorders. Clin Genet1978; 13: 425–442
Smith RJH. Branchiootorenal Spectrum Disorders. GeneReviews® 1999 March 19 (Updated 2013 June 20)

Alport Syndrome
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk relatives
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Alport syndrome is characterized by renal, cochlear, and ocular involvement. The main manifestation is glomerular nephropathy with hematuria, progressing to end-stage renal disease. Eye abnormalities include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The hearing loss develops gradually and is usually detectable during late childhood or early adolescence.

Prevalence of Alport syndrome is estimated at 1/50 000.

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5 genes. The disease is known to be inherited in an X-linked, autosomal recessive or autosomal dominant pattern.

References:

Clifford EK. Alport Syndrome and Thin Basement Membrane Nephropathy. GeneReviews® 2001 Aug 28 (Updated 2013 Feb 28)
Hertz JM et al. Clinical utility gene card for: Alport syndrome. European Journal of Human Genetics. 2012. 20 doi:10.1038/ejhg.2011.237 (Updated 2014 Nov 12)

Mitochondrial Diseases
Mitochondrial genome sequencing

Nuclear genes of NGS panel

Single gene sequencing

MELAS Syndrome targeted mutation analysis

Deletion/duplication analysis

Indications for genetic testing:

1. Diagnosis of patients with phenotype characteristic for mitochondrial disease
2. Diagnosis of patients with family history suggestive for mitochondrial disease
3. Genetic counseling of individuals with mitochondrial disease and affected family members

Mitochondrial diseases are a genetically and clinically heterogeneous group of disorders that arise as a consequence of dysfunction of the mitochondrial respiratory chain. The estimate for the prevalence of all mitochondrial disorders 1:8500, but they are thought to be greatly under-diagnosed. Mitochondrial disorders can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). If nuclear gene defects may be inherited in an autosomal recessive or autosomal dominant manner, mtDNA defects are transmitted only maternally. As the female could have heteroplasmic mtDNA mutations, which could be transmitted unequally to her offspring, the sibs could exhibit considerable clinical variability.

Symptoms of the mitochondrial disease can begin at any age. Mitochondrial disorders may affect a single organ (e.g. Leber hereditary optic neuropathy, LHON) or involve multiple organ systems (e.g. Myoclonic epilepsy with ragged-red fibers, MERRF). Common clinical features of mitochondrial disorder include, for example muscle weakness, exercise intolerance, trouble with balance and coordination, sensorineural deafness, impaired vision, seizures and learning deficits, cardiomyopathy, diabetes mellitus, stunted growth, and a high incidence of mid- and late pregnancy loss.

References:

Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999;283:1482–8.
Chinnery PF. Mitochondrial Disorders Overview. Pagon RA, Adam MP, Bird TD, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2013.
DiMauro S, Schon EA. Nuclear power and mitochondrial disease. Nat Genet. 1998;19:214–5.
Leonard JV, Schapira AVH. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet. 2000a;355:299–304.
Leonard JV, Schapira AVH. Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects. Lancet. 2000b;355:389–94.

Menkes Disease
Sequencing of the ATP7A gene 

Deletion/duplication analysis of the ATP7A 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

Menkes disease is a disorder of copper metabolism characterized by growth failure, developmental delay and progressive neurodegeneration. Patients with Menkes disease may also present hair changes (short, sparse, coarse, twisted hair, and colorless or steel-colored), hypothermia, hypoglycemia, hypotonia, and seizures. Onset of Menkes disease typically begins in the neonatal period.

Menkes disease is caused by mutations in the ATP7A gene. The disorder is inherited in an X-linked recessive pattern.

The incidence of Menkes disease is estimated to be 1 in 100,000 to 360,000 newborns.

Charcot-Marie-Tooth Disease
NGS panel

Deletion/duplication analysis 

Indications for genetic testing:

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

Charcot-Marie-Tooth disease (CMT) also known as Charcot–Marie–Tooth neuropathy is a heterogeneous group of disorders characterized by distal muscle weakness and atrophy and loss of sensation in the feet and/or hands. Usually, the initial symptoms are foot deformities, such as high arches and hammertoes and “inverted champagne bottle” appearance of the lower parts of the legs. Weakness and muscle atrophy may occur in the hands as the disease progresses. Other symptoms of the disease may include hearing loss and scoliosis.

Prevalence of CMT hereditary neuropathy is about 1:2500.

Based on clinical manifestations and affected genes, CMT can be divided into types and subtypes. The most common form of CMT is Charcot-Marie-Tooth type 1A caused by duplication of or mutation in the PMP22 gene.

CMT neuropathy can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

Familial Thoracic Aortic Aneurysm and Dissection
and Related Syndromes
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Differential diagnosis of familial TAAD, Marfan syndrome, Loeys-Dietz syndrome and genetically/phenotypically related disorders
3. Predictive testing for at-risk asymptomatic family members
4. Prenatal diagnosis for known familial mutation
5. Genetic counseling

Familial Thoracic Aortic Aneurysm and Dissection (TAAD) is characterized by enlargement of ascending aorta leading to an aortic dissection or, rarely, aortic rupture. Aortic dilatation is usually the first manifestation of the disease that may lead to the development of aortic aneurysm and aortic dissection. Aortic dissection occurs when the tear in the aorta wall allows blood to flow between the aorta’s inner and outer walls. Aortic dissections originate primarily in the ascending aorta (Stanford type A), but also can occur in the descending thoracic aorta (Stanford type B).

Thoracic aortic aneurysms may be asymptomatic. Aneurysms and dissections can occur as an isolated cardiovascular abnormality or are related to genetic disorders such as Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, and others.

Familial TAAD is inherited in an autosomal dominant pattern. Up to 19% of persons with TAAD have a first-degree relative with thoracic aortic disease.

References:

Albornoz G et al. Familial thoracic aortic aneurysms and dissections–incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006;82:1400–5.
Milewicz DM and Regalado E. Thoracic Aortic Aneurysms and Aortic Dissections. GeneReviews® 2003 February 13 (Updated 2012 January 12).

Familial Hypercholesterolemia
NGS panel

Deletion/duplication analysis of the LDLR gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Carrier testing for known familial mutations
3. Genetic counseling

Familial hypercholesterolemia (FH) is characterized by high LDL (low density lipoprotein) cholesterol level that cause atherosclerotic plaque deposition in the coronary arteries, increasing the risk for early cardiovascular disease and stroke.

Deposition of cholesterol is also found in the tendons of the hands, elbows, knees and feet (xanthomas) and around the eyes (xanthelasmas).

Heterozygous FH is associated with heterozygous pathogenic variant in one of three genes – LDLR, APOB, PCSK9, and occurs at a frequency of about 1:500. Homozygous FH is much rarer, occurring in about 1:1,000,000 in general population. Homozygous FH results from biallelic mutations in one of the following genes: LDLR, LDLRAP1, APOB, PCSK9.

References:

Civeira F et al. Spanish Familial Hypercholesterolemia Group.; Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation. Arterioscler Thromb Vasc Biol. 2005;25:1960–5.
Khachadurian AK, Uthman SM (1973). “Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients”. Nutr Metab 15 (1): 132–40.
Nordestgaard BG et al. European Atherosclerosis Society Consensus Panel.; Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34:3478–90.
Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223:262–8.
Rader DJ et al. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111(12):1795–803.
Varret M et al. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008:73:1–13.

Brugada Syndrome
NGS panel

Deletion/duplication analysis of the SCN5A gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Risk assessment of at-risk relatives
3. Prenatal diagnosis for known familial mutation
4. Differential diagnosis of Brugada syndrome from other genetic heart conditions
5. Genetic counseling

Brugada syndrome, caused by an ion channelopathy, is characterized by ST-segment abnormalities in leads V₁-V₃ on ECG and an increased risk of sudden death in patients with structurally normal hearts. Brugada syndrome manifests predominantly during adulthood, in patients between ages 20 to 40.

Symptoms include ventricular arrhythmia, syncope, and cardiac arrest usually during sleep or rest. In some patients sudden cardiac death may occur without any sign of clinical symptoms. Brugada syndrome may overlap with conduction disease. Symptoms such as first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome could be included in a differential diagnosis.

The prevalence of Brugada syndrome is estimated to affect 5 in 10,000 people worldwide. Although Brugada syndrome affects both men and women, the condition is more prevalent among men.

Brugada syndrome is inherited in an autosomal dominant manner.

References:

Antzelevitch C et al. Brugada Syndrome. Report of the second consensus conference. Heart Rhythm 2005; 2 (4): 429–440
Brugada R et al. Brugada Syndrome. GeneReviews® 2005 Mar 31 (Updated 2014 Apr 10).
Fowler SJ, Priori SG. Curr Opin Cardiol. 2008; 24:74-81. 

Long QT Syndrome
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Distinguishing different forms of LQTS to direct appropriate therapies
3. Testing of family members of the affected individuals
4. Carrier status detection of known mutation
5. Genetic counseling

Long QT Syndrome (LQTS) is a rare hereditary disease that is characterized by a prolonged QT-interval on the electrocardiogram (ECG) due to delayed repolarization of the heart. Affected individuals have an increased risk for ventricular tachycardia with syncope or even sudden death due to ventricular fibrillation.

The estimated prevalence of LQTS is one in 2000. The clinical symptoms of LQTS are quite variable depending on the causative mutation, age, gender, environmental factors and therapeutic interventions. The age of onset is usually younger than 40 years of age, however, the condition can occur as early as in infancy. The diagnosis and risk assessment of LQTS is based on patient’s clinical symptoms, including ECG findings, as well as family history. However, the diagnosis of LQTS can be challenging since around 2.5% of the healthy population have prolonged QT-interval while some of LQTS patients do not exhibit abnormal ECG findings. Therefore, genetic testing is a valuable component in the assessment of LQTS patients.

LQTS is caused by mutations in genes encoding for the subunits of various ion channels. To date, over 600 disease causing mutations have been recognized in at least 15 genes. It has been shown that mutations in known LQTS related genes can be detected in more than 75% of patients with clinical diagnosis. Most commonly the mutations are detected in KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) genes and account for about 95% of mutations in affected individuals. The disorder is inherited as an autosomal dominant trait, although a rare subtype with autosomal recessive inheritance has been reported (Jervell and Lange-Nielsen Syndrome).

References:

Lehnart SE et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007 Nov 13;116(20):2325-45. 
Moric-Janiszewska E et al. Challenges of diagnosis of long-QT syndrome in children. Pacing Clin Electrophysiol. 2007 Sep;30(9):1168-70.
Morita H et al. The QT syndromes: long and short. Lancet. 2008 Aug 30;372(9640):750-63.
Tester DJ, Ackerman MJ. Genetics of long QT syndrome. Methodist Debakey Cardiovasc J. 2014 Jan-Mar;10(1):29-33.
Schwartz PJ. Prevalence of the congenital long-QT syndrome. Circulation. 2009 Nov 3;120(18):1761-7.
Wang et al. The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R). Heart Rhythm. 2013 Oct;10(10):1500-6.

Cancer Predisposition
NGS panel

Indications for genetic testing:

1. 1. Testing of individuals with early-age-onset of cancer
   2. Testing of individuals with multiple primary cancers
   3. Testing of family members of the affected individuals
   4. Testing individuals with family history suggesting inherited pattern of cancer but no genetic changes identified previously
   5. Genetic counseling

Determination of cancer predisposition is vital for prevention and early detection of the disease. Early diagnosis of cancer will ensure the immediate start of treatment, which is a key to increasing the survival and recovery. Significant difference between the survival rates of early stage and advanced stage of cancer points out the need for risk assessment of the disease.

Identification of genetic susceptibility to hereditary cancer syndromes enables to implement risk-reduction strategies, estimate familial cancer risk and identify at-risk family members.

Cancer predisposition testing includes NGS panel and deletion/duplication analysis, allowing us to analyze multiple genes associated with an increased risk for a wide range of cancers.

Polyposis Syndromes
NGS panel

Del/dup analysis

Indications for genetic testing:

1. 1. Confirmation of clinical diagnosis
   2. Testing of individuals with family history of polyposis syndromes
   3. Differentiation of FAP from MUTYH-associated polyposis
   4. Differentiation of juvenile polyposis from other hamartomatous polyposis syndromes
   5. Genetic counseling

Numerous polyposis syndromes may present with gastrointestinal (GI) polyps. Hereditary types include familial adenomatous polyposis and hamartomatous polyposis, and other rare polyposis syndromes. Molecular genetic testing enables differential diagnosis of GI polyposis syndromes often defined with overlapping and indistinguishable phenotypes.

Familial adenomatous polyposis (FAP), MUTYH-associated polyposis, BMPR1A-related juvenile polyposis, SMAD4-related juvenile polyposis, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome are included in the testing.

 

References:

Bronner MP. Gastrointestinal Inherited Polyposis Syndromes. Mod Pathol 2003;16(4):359–365
Jasperson KW, Burt RW. APC-Associated Polyposis Conditions. GeneReviews® 1998 December 18 (Updated 2014 March 27).

Sensorineural Hearing Loss
NGS panel

Targeted regions sequencing

Sequencing of the GJB2 gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Determination of molecular genetic basis both of nonsyndromic and/or syndromic SNHL
3. Distinguish different forms of nonsyndromic hearing loss and deafness
4. Define etiology of hearing loss after aminoglycoside therapy
5. Detection the carrier status of individuals with family history of maternally-inherited hearing loss with or without aminoglycoside therapy
6. Detection the carrier status of relatives with a known mutation
7. Genetic counseling
8. Prenatal diagnosis

Hereditary sensorineural hearing loss (SNHL) includes syndromic and non-syndromic forms. The syndromic forms of SNHL include Usher syndrome, Pendred syndrome, Waardenburg syndrome, Jervell and Lange-Nielsen syndromes, etc. Most cases of SNHL are nonsyndromic. SNHL can follow a pattern of autosomal dominant, autosomal recessive, x-linked recessive, or mitochondrial inheritance.

Breast and Ovarian Cancer
NGS panel

Sequencing of BRCA1, BRCA2 genes

Del/dup analysis 

Indications for genetic testing:

1. Testing of individuals with early-age-onset of breast or ovarian cancer
2. Testing of individuals with family history of breast or ovarian cancer
3. Testing of at-risk family members for known mutations
3. Genetic counseling

Testing should be performed if there is a family history of breast or ovarian cancer, genetic alterations have been found in the family, or there is a history of breast cancer in males in the family.

Breast and ovarian cancers are most strongly associated with mutations of the BRCA1 and BRCA2 genes. Among women who have a clinically important BRCA gene mutation, the lifetime risk of developing breast and/or ovarian cancer can reach 80%. Cancer-predisposing mutations in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant manner. The prognosis for breast cancer survival depends upon the stage at which breast cancer is diagnosed.

Combined Pituitary Hormone Deficiency
NGS panel

Deletion/duplication analysis

Optic Atrophy
NGS panel

Targeted regions sequencing

Deletion/duplication analysis of the OPA1 gene

Indications for genetic testing:

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

Optic atrophy 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 to complete blindness. The age of onset is usually between 4 and 6 years, but optic atrophy rarely causes severe vision impairment in childhood.

Flexible approach to gene panels

In diagnosing complex disorders, it may be necessary to use wider range of genes than initially determined, or combine different gene panels. We can easily redesign our existing gene panels to match your clinical practice or research project. Additional fee will not be added. Contact info[at]asperbio.com to ask for personal solutions.

Pre- and post-test consultation by email/phone/Skype

Medical geneticist is available for pre- and post-test consultation (60 €) to referring physicians and health-care professionals. Contact info[at]asperbio.com to register for consultation.

Hypothyroidism and Thyroid Hormone Resistance
NGS panel

Deletion/duplication analysis

Genetic testing at Asper Biogene

Genetic testing services offered by Asper Biogene comply with the highest level quality standards and are certified by Clinical Laboratory Improvement Amendments (CLIA) and ISO 15189:2012. We regularly participate in external quality assurance schemes to maintain the highest level of testing services.

Single mutation analysis

Single mutation analysis for any familial or known mutation.

Single gene sequencing

Sequencing of the entire coding region of any single gene.

Targeted regions sequencing

Targeted regions sequencing includes the analysis of selected hotspot regions in disease associated genes.

Deletion/duplication analysis

Deletion/duplication analysis for the genes listed in our test menu.

Next generation sequencing (NGS) panels

Our testing menu includes a wide variety of carefully constructed NGS panels. Essential medical specialities are covered by our clinically relevant, validated, and up-to-date gene panels. NGS panels include the sequencing of entire coding regions plus flanking intronic regions. Likely pathogenic and pathogenic variants are confirmed by Sanger sequencing.

In addition, CNV analysis based on sequencing coverage depth data is also available. Likely pathogenic and pathogenic findings are confirmed using another technology such as aCGH, qPCR, or MLPA when applicable. 

We upgrade the existing gene panels continuously as well as create additional ones based on new scientific knowledge and customer requests. 

Customized NGS panels

In addition to ready-to-use tests, we develop and implement custom-made tests and solutions to meet our customers’ specific needs. 

Existing NGS panels are easily adjustable for your clinical practice and patients’ indications.

For customized NGS panels, fill in the Custom test order form or ask for more information on redesigning solutions for additional panels.

Whole exome sequencing (WES)

WES includes the sequencing of coding regions and their flanking intronic regions in approximately 20,000 genes of the human genome. The coding region represents 1–2% of the human genome but contains approximately 85% of the disease-causing mutations. Phenotype/diagnosis associated likely pathogenic and pathogenic variants are confirmed by Sanger sequencing.

CNV analysis based on sequencing coverage depth data is available as an expanded testing option. Likely pathogenic and pathogenic findings are confirmed using another technology such as aCGH, qPCR, or MLPA when applicable.

WES is an effective option to detect the rare causal variants of Mendelian disorders. Service can be useful for clinicians to diagnose affected patients with conditions that have eluded traditional diagnostic approaches.

Whole genome sequencing (WGS)

WGS determines the complete DNA sequence of an individual’s genome, including chromosomal DNA and mitochondrial DNA.

WGS covers the sequencing of the entire coding and non-coding regions of the genome. WGS enables detection of non-coding sequence variants that could be informative in diagnosing genetically and phenotypically heterogeneous or undiagnosed diseases. WGS can reveal the full range of variations, including single nucleotide variations, copy number variations, changes in transposable elements, and structural variations.

Phenotype/diagnosis associated likely pathogenic and pathogenic variants are confirmed by Sanger sequencing.

Trio exome or genome sequencing of family members (usually affected child with parents) is highly recommended for faster and more precise identifying of disease-causing mutations and determining the inheritance pattern. In addition to the patient’s phenotype/disease associated variants, incidental findings are reported according to  ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Bioinformatic analysis and interpretation of customer’s genetic data

Asper Biogene’s qualified geneticists analyze and interpret your sequencing data, deletion/duplication analysis results etc.

Ask for a customized solution from our experienced team to facilitate your clinical practice.

Results report

Our results report contains detailed information on the detected variants, including bioinformatics analysis, biological interpretation, comprehensive clinical interpretation and recommendations for follow-up analyses. Rare and known pathogenic variants are assessed and classified according to the standards and guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Confirmation of likely pathogenic or pathogenic variants is performed by Sanger sequencing.