Asper Biogene – genetic testing company

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 

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.

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)

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.

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)

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.

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.

Oculocutaneous Albinism, Ocular Albinism, Hermansky-Pudlak Syndrome, Chediak-Higashi Syndrome
NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. 1. Confirmation of clinical diagnosis
   2. Differential diagnosis of different forms/subtypes of Oculocutaneous albinism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome and other genetically/phenotypically related disorders
   3. Prenatal diagnosis for known familial mutation
   4. Genetic counseling

   Oculocutaneous albinism (OCA) is a group of rare inherited disorders characterized by a reduction or complete lack of melanin pigment in the skin, hair and eyes. These conditions are caused by mutations in specific genes that are relevant to the production of melanin pigment in melanocytes. Patients usually have vision problems such as reduced sharpness, nystagmus and photophobia. There are seven types of OCA (OCA1-7) caused by mutations in seven different genes.

   Ocular albinism (OA) primarily affects the eyes, and does not significantly affect the color of the skin and hair. The most common form of OA is type 1 (OA1), also named X-linked ocular albinism. OA1 is characterized by vision abnormalities in affected males. Vision deficits are present at birth and do not become more severe over time. Other forms of OA are much rarer and may be associated with additional signs and symptoms such as hearing loss.

   Hermansky-Pudlak syndrome (HPS) is a multisystem, hereditary disorder characterized mainly by albinism with visual impairment and blood platelet dysfunction with prolonged bleeding. The symptoms of HPS are present at birth. It is the third most prevalent form of albinism. There are 11 types of HPS (1-11), which can be distinguished by their signs and symptoms and underlying genetic cause.

   Chediak-Higashi syndrome (CHS) is an inherited, complex, immune disorder that usually occurs in childhood (at birth or shortly thereafter) characterized by oculocutaneous albinism, nervous system abnormalities, immune deficiency with an increased susceptibility to infections, and a tendency to easy bruising and abnormal bleeding.

   The test covers known genetic causes of all aforementioned syndromes.

   Oculocutaneous albinism, Hermansky-Pudlak syndrome, and Chediak-Higashi syndrome are inherited in an autosomal recessive inheritance pattern. Ocular albinism type 1 is inherited in an X-linked pattern.

   Oculocutaneous albinism occurring in all populations, with an estimate prevalence of 1:20 000 people worldwide. Ocular albinism type 1 affects at least 1: 60 000 males. Hermansky-Pudlak syndrome is estimated to affect 1:500 000 to 1 000 000 individuals worldwide. Type 1 is more common in the northwestern part of Puerto Rico where about 1: 1800 people are affected. Type 3 is common in people from central Puerto Rico. Chediak-Higashi syndrome is a very rare disorder. About 200 cases of the condition have been reported worldwide. 85% of affected individuals progress the accelerated phase.

   References:
   Hayashi M, Suzuki T. Oculocutaneous Albinism Type 4. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; November 17, 2005. PMID:20301683
   Huizing M, Malicdan MCV, Gochuico BR, et al. Hermansky-Pudlak Syndrome. 2000 Jul 24 [Updated 2017 Oct 26]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. PMID: 20301464
   Huizing M, Malicdan MCV, Wang JA, et al. Hermansky-Pudlak syndrome: Mutation update. Hum Mutat. 2020;41(3):543-580. doi:10.1002/humu.23968. PMID:31898847
   Lewis RA. Oculocutaneous Albinism Type 1. 2000 Jan 19 [Updated 2013 May 16]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. PMID:20301345
   Lewis RA. Oculocutaneous Albinism Type 2. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; July 17, 2003. PMID: 20301410
   Lewis RA. Ocular Albinism, X-Linked. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; March 12, 2004. PMID:20301517
   Merideth MA, Introne WJ, Wang JA, O’Brien KJ, Huizing M, Gochuico BR. Genetic variants associated with Hermansky-Pudlak syndrome. Platelets. 2020;31(4):544-547. doi:10.1080/09537104.2019.1663810. PMID:32436471
   Pennamen P, Le L, Tingaud-Sequeira A, et al. BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak syndrome [published online ahead of print, 2020 Jun 22]. Genet Med. 2020;10.1038/s41436-020-0867-5. doi:10.1038/s41436-020-0867-5. PMID:32565547
   Toro C, Nicoli ER, Malicdan MC, Adams DR, Introne WJ. Chediak-Higashi Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; March 3, 2009. PMID:20301751

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.

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.

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).

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).

Lynch Syndrome
NGS panel

Single Gene Sequencing

Deletion/duplication analysis

Referral for molecular testing of Lynch syndrome:

1. Tumour tissue analysis to evaluate the MMR proteins expression by immunohistochemical analysis (IHC) and DNA microsatellite instability (MSI) testing is suggested for the individuals meeting Amsterdam II/Bethesda criteria.
2. If absence of the MLH1/PMS2 proteins expression is observed by IHC, methylation analysis of the MLH1 gene promoter and/or testing of the somatic BRAF V600E mutation is recommended in order to exclude sporadic colorectal cancer cases.
3. If tumour with MMR deficiency and MSI high is detected, further mutation analysis from peripheral blood/normal tissue of the MMR genes is indicated.

Indications for mutation analysis:

1. 1. Testing of individuals meeting Amsterdam II/Bethesda criteria
   2. Testing of individuals with family history of colorectal cancer or other Lynch syndrome-related cancers
   3. Testing of at-risk family members for known mutations
   4. Genetic counseling

Lynch syndrome, also called hereditary non-polyposis colon cancer (HNPCC), is characterized by an increased risk of colon cancer and other cancers (e.g., of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin). Lynch syndrome is inherited in an autosomal dominant manner and it is associated with germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have a lifetime risk of up to 80% for colorectal cancer, 20-60% risk of endometrial cancer, as well as other tumors. Lynch syndrome is associated with early onset of cancer, the average age of diagnosis is 45 years.

Familial Adenomatous Polyposis
Sequencing of the APC gene

Del/dup analysis of the APC gene

Indications for mutation analysis:

1. Testing of individuals with adenomatous polyps
2. Testing of first degree relatives of the affected individuals
3. Genetic counseling

Familial adenomatous polyposis (FAP) is a colon cancer predisposition syndrome characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. By age 35, 95% of individuals with FAP have polyps. If left untreated, patients with this syndrome develop colon cancer by age 35-40. APC-associated polyposis conditions are inherited in an autosomal dominant manner.

 

Cystic Fibrosis
Sequencing of the CFTR gene

Deletion/duplication analysis of the CFTR gene

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Carrier testing for family members of CF patients
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Cystic fibrosis (CF) is an autosomal recessive, multisystem disease. CF is characterized by recurrent lung infections, malabsorption, malnutrition, and male infertility. Cystic fibrosis is caused by thick and sticky mucus due to disturbances of salt homeostasis in cells.

CF is caused by mutations in the CFTR gene encoding cystic fibrosis transmembrane conductance regulator protein. The CFTR protein functions as a chloride channel expressed on epithelial cell membranes and controls the regulation of other transport pathways.

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.

Familial Hypocalciuric Hypercalcemia
Sequencing of the CASR gene

Deletion/duplication analysis of the CASR gene

Autosomal Dominant Retinitis Pigmentosa NGS panel

Deletion/duplication analysis

Indications for genetic testing:

1. Confirmation of clinical diagnosis
2. Testing of individuals in subsequent generations with family history of autosomal dominant retinitis pigmentosa
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Retinitis pigmentosa is an inherited retinal dystrophy caused by the loss of photoreceptors 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 visual problems do not usually develop until early adulthood. In some cases, RP is characterized by cone-rod dystrophy, in which the decrease in visual acuity predominates over loss of the visual field. RP is usually nonsyndromic but there are also many syndromic forms. The main risk factor is a family history of retinitis pigmentosa.

Hypothyroidism and Thyroid Hormone Resistance
NGS panel

Deletion/duplication analysis