OTHER HEREDITARY DISEASES

It is a multi-organ disease; the lungs, digestive tract, pancreas, sweat glands, and the male reproductive tract are affected. The disease is caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Regulator) gene. More than 2000 mutations in this gene have been described worldwide, the most common of which is the F508del mutation. The tested mutations represent almost 91% of all mutations in patients with cystic fibrosis in the Czech Republic. If both parents are carriers of the CFTR gene mutation, the risk of CF for their future children is 25%. To ensure the prevention of CF in their offspring, prenatal diagnosis (from chorionic villi or amniotic fluid) is performed, and preimplantation diagnosis is also possible.

Gene, specification: CFTR gene (50 mutations)

Type of material to be examined: blood

Indicating specialists: medical genetics

The affected people have varying degrees of mental retardation and are described as having various severe behavioural disorders such as learning disabilities, autism and hyperactivity. The manifestation of the phenotype in prepubertal boys is relatively non-specific and variable, which makes clinical diagnosis difficult.

Women can also be affected, with about half of the full mutation carriers having mild to moderate mental retardation. The syndrome occurs with a frequency of approximately 1 : 4,000 to 3 : 4,000 for men and 1 : 8,000 for women. Fragile X syndrome is caused in most cases by a dynamic mutation - expansion of CGG trinucleotides over 200 repeats in the 5'-untranslated region of the FMR1 gene at Xq27.3. Subsequent abnormal hypermethylation of the promoter region causes silencing of FMR1 gene expression. As a result of the mitotic instability of the mutation, some patients show somatic mosaicism (coexistence of premutation and full mutation), which explains the great variability of clinical manifestation.

In the normal form of the FMR1 gene, the number of repeats (CGG)n varies between 6 and 44 with 1-3 AGG triplet breaks, with the most common alleles in the population having 29-30 repeats. Intermediate alleles with a repeat range of 45-54 form a grey zone - carriers have healthy children, but there is a risk of developing of an allele with the full mutation in subsequent generations.

Alleles with a range of 55-200 repeats without abnormal methylation are referred to as premutations. Carriers of premutation are not affected by mental retardation, but it causes two quite different diseases with low penetrance, fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian failure in women, which affects about 20% of female premutation carriers. Premutations are unstable during meiosis or early embryogenesis, and if they are transmitted by a female, there is a risk of expansion of the CGG repeat into a full mutation. In contrast, male-transmitted premutations only rarely expand into a full mutation. The risk of a full mutation depends on the length of the maternal premutation and is present in more than 95% of alleles with more than 100 repeats. The shortest allele that has been described to expand into a full mutation in one generation has 59 repeats without an AGG break. The frequency of mutant alleles in the population is given as 1 : 100-300 for women and 1 : 250-800 for men.

Gene, specification: FMR1 gene

Type of material to be examined: blood

Indicating specialists: medical genetics

The SMN (Survival Motor Neuron) protein regulates motor neuron survival, and its deficiency causes progressive proximal muscle weakness and atrophy. The cause of SMA is a mutation in the SMN gene, with more than 95% of patients having a homozygous biallelic deletion of exon 7 in the SMN1 gene. Carriers typically have one normal and one mutated copy and show no symptoms. Thus, determining the number of the SMN1 gene copies allows the detection of most SMA carriers before the birth of an affected child. SMN2 is a highly homologous pseudogene; most of its transcripts lack exon 7 due to the 840C›T substitution. The protein produced by this gene is not sufficient to prevent the disease, but it is sufficient to modify the phenotype. Determining the number of copies of the SMN2 gene is important for SMA patients because the more copies a patient has, the milder the symptoms of the disease.

Gene, specification: SMN1, SMN2 genes (MLPA)

Type of material to be examined: blood

Indicating specialists: medical genetics

The AZF locus is divided into three subregions: AZFa, AZFb, AZFc. Genes occurring in this region are involved in the process of spermatogenesis and are essential for male reproduction. It is believed that each subregion is active at a different stage of spermatogenesis. A certain correlation between the severity of the disorder and the localization of the microdeletion was observed. If microdeletion occurs in the AZFb and AZFc subregion, then its phenotypic expression varies from azoospermia to oligozoospermia. Microdeletion in the AZFa area has a much more serious manifestation, namely the complete absence of spermatogonia. When microdeletion is detected, the use of microsurgical sperm aspiration/extraction (MESA, TESE) and the ICSI method of assisted reproduction is recommended. Since microdeletions in the AZF region are inherited from father to son in 100%, preimplantation sex selection can be considered when a Y chromosome deletion is detected. The SRY gene determines male sex, inducing the production of testosterone, which is necessary for the development of testes and secondary male sex characteristics. Mutations in this gene cause the development of the female phenotype (female 46, XY), which is associated with gonadal dysgenesis.

Gene, specification: AZFa, AZFb, AZFc gene regions, including the SRY gene.

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, 613 gynaecology and obstetrics group 1, 603 gynaecology and obstetrics, urology

Microdeletion/microduplication syndromes are inherited in an autosomal dominant pattern, but the majority of cases arise de novo. Genetic heterogeneity is common, and the responsible genes may be located on different chromosomes (e.g., DiGeorge syndrome on both 22q and 10q). Some microdeletion syndromes can result not only from a deletion but also from a point mutation (e.g., Rubinstein-Taybi syndrome, 10% from a microdeletion and 90% from a point mutation).

The deletion often affects multiple important genes, called contiguous gene syndromes. The test detects the following syndromes: microdeletion syndrome 1p36 (Slavotinek syndrome), microdeletion syndrome 2p16.1-p15, 2q23.1 microdeletion/microduplication syndrome, Glass syndrome (2q32-q33), microdeletion syndrome 3q29, microduplication syndrome 3q29, Wolf-Hirschhorn syndrome (4p16.3), cri-du-chat syndrome (5p15), Sotos syndrome (5q35.3), Williams-Beuren syndrome (7q11.23), Williams-Beuren duplication syndrome (7q11.23), Langer-Giedion syndrome (8q24.12-q24.13), microdeletion syndrome 9q22.3, DiGeorge syndrome-2 (10p13-p14), Prader-Willi syndrome/Angelmann syndrome (15q11.2), microdeletion syndrome 15q24, Rubinstein-Taybi syndrome (16p13.3), Miller-Dieker syndrome (17p13.3), lissencephaly-1 (17p13.3), Smith-Magenis syndrome (17p11.2), Potocki-Lupski syndrome (17p11.2), NF1 microdeletion syndrome (17q11.2), Koolen-de Vries syndrome (17q21.31), microduplication syndrome 17q21.31, DiGeorge microdeletion syndrome (22q11.21), microduplication syndrome 22q11.2, Phelan-McDermid microdeletion syndrome (22q13), Rett syndrome (Xq28), MECP2 duplication syndrome (Xq28), X chromosome copy number changes, probes for Y chromosome microdeletion detection.

Gene, specification: MLPA SALSA® MLPA® probemix P245

Type of material to be examined: peripheral blood, chorionic villi, amniotic fluid

Indicating specialists: medical genetics

In the Czech Republic, approximately 7-8% of the population suffers from osteoporosis. Osteoporosis has a complex aetiology. Many factors are involved in the disease, such as diet, lifestyle, and hormonal influences, but there is also a strong genetic component. Several polymorphisms have now been described that are associated with bone loss and thus an increased risk of osteoporosis. Osteoporosis can also occur as a consequence of an underlying, usually endocrinological disease (e.g., thyroid disease), chronic liver or kidney disease, as a consequence of diabetes, or with long-term use of certain medications (e.g., corticosteroids). In this case, we are talking about secondary osteoporosis.

Gene, specification: Genes: COL1A1, c.104-441G>T; VDR, c.1174+283G>A

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics

The disease leads to kidney failure. The typical finding is that of enlarged kidneys permeated with cysts. Already at the stage of normal renal function, hypertension is present in up to 70% of patients. Other renal complications include urinary tract infections, nephrolithiasis, haematuria, bleeding into cysts. ADPKD is a systemic disease with frequent extrarenal manifestations. Most often, these are cysts in other organs (liver, possibly pancreas, spleen). 

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited and severe form of polycystic kidney disease affecting the kidneys and biliary tract with an estimated incidence of 1 : 20,000 live births. The disease is caused by mutations in the PKHD1 gene (on chromosome 6c) and it is necessary to carry two mutations in this gene to manifest the disease. Carriers of only one mutation are therefore completely healthy. 

Gene, specification:  PKD1, PKD2, PKHD1 genes 

Type of material to be examined: blood

Indicating specialists: medical genetics 

Chronic pancreatitis is a disease in which the functional parenchyma of the gland is replaced by connective tissue, and exocrine and endocrine pancreatic insufficiency gradually occurs. Many factors may be involved in the development of chronic pancreatitis, but genetic factors play a major role in the etiopathogenesis of the disease. A genetic form of chronic pancreatitis is hereditary pancreatitis, where intrapancreatic trypsinogen is autoactivated, inducing inflammation and developing chronic inflammation.

Most often it occurs in the form of recurrent attacks of acute pancreatitis, the recurrent form then passes to the chronic stage, and secondary diabetes may develop. The clinical picture varies in symptoms from lack of appetite and mild abdominal pain to life-threatening conditions. It is an important risk factor for pancreatic cancer.

Mutations in the PRSS1, PRSS2 and SPINK1 genes have been associated with hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant disease with incomplete penetrance and variable expressivity. If a hereditary form of chronic pancreatitis is suspected, molecular genetic testing of the CFTR gene may also be performed in the context of cystic fibrosis.

INDICATIVE CLINICAL CRITERIA
Familial forms
• at least two direct relatives with acute recurrent/chronic pancreatitis of unclear aetiology
• at least two direct relatives with acute recurrent/chronic pancreatitis and pancreatic cancer under 60 years of age
• presence of a known familial mutation in genes related to hereditary pancreatitis
Sporadic forms
• acute recurrent/chronic pancreatitis in childhood
• acute recurrent/chronic pancreatitis without an apparent underlying cause with severe clinical course and findings of pancreatic calcifications/pseudocysts under the age of 50
• pancreatic cancer on the basis of chronic pancreatitis under the age of 50

Gene, specification: PRSS1, PRSS2, SPINK1 genes

Type of material to be examined: blood

Indicating specialists: medical genetics

Congenital nonsyndromic hearing loss is genetically very heterogeneous, and dozens of genes responsible for nonsyndromic hearing loss have been described. The inheritance is most often autosomal recessive and in more than half of the cases is caused by germline mutations in the GJB2 gene (13q12.11). The detection of two pathogenic mutations in the GJB2 gene leads to molecular genetic confirmation of the diagnosis. The frequency of healthy carriers of a single pathogenic mutation in the GJB2 gene is up to 1 : 31 (up to 3% of the population worldwide). In addition to autosomal recessive inheritance, nonsyndromic hearing loss also has autosomal dominant inheritance, to a minor extent also X-linked and mitochondrial inheritance. Genetic counselling and testing for suspected non-syndromic hearing loss can be offered at any age.

Gene, specification: Gen GJB2

Type of material to be examined: blood

Indicating specialists: medical genetics

As a result, copper accumulates in various tissues of the body, especially the brain and liver, and subsequently damages them. Clinically, we distinguish between neurological and hepatic forms, but the manifestations of the disease are very diverse. The ATP7B gene is located in the 13q14.3 region and is expressed mainly in hepatocytes, kidney, placenta, brain, heart, muscle and pancreas. More than 200 mutations of the ATP7B gene have been published so far. Wilson's disease is treatable (appropriate diet, penicillamine and zinc preparations). Early initiation of lifelong therapy is very effective, and the disease has an excellent prognosis in this case. Unrecognized disease leads to irreversible liver and brain damage. Genetic testing is particularly useful in siblings of patients with proven Wilson's disease and in the asymptomatic phase of the disease. The most common form of hepatic manifestation is liver cirrhosis with a tendency to rapid progression; therefore, all etiologically unclear liver cirrhosis in persons younger than 45 years should be examined for the possibility of Wilson's disease.

Gene, specification:  ATP7B gene

Type of material to be examined: blood

Indicating specialists: medical genetics

The disease is manifested by diarrhoea, abdominal pain, impaired digestion and absorption (malabsorption), general symptoms (fatigue, increased temperature, etc.) and extra-intestinal symptoms (joint pain and inflammation, aphthous stomatitis, skin problems). The exact cause of Crohn's disease is still unknown. The predisposition to the disease is genetically influenced and the disease can be triggered by environmental factors (e.g., dietary errors, smoking, stress). Immunological and infectious factors are also involved in the development of the disease (all of which are the subject of intensive research).

Recently, several chromosomal regions have been identified that show possible association with susceptibility to Crohn's disease. One important gene whose mutations are associated with an increased likelihood of developing Crohn's disease is the NOD2/CARD15gene, which is located on chromosome 16q12. The protein encoded by this gene plays an important role in the immune response to bacterial infection. Mutations in this gene result in a change in the function of the protein and result in a loss of control of the organism over the bacterial infection.

Three mutations in the NOD2/CARD15 gene (c.2104C>T, c.2722G>C, c.3019_3020insC) account for approximately 82% of mutations occurring in Crohn's disease patients. The relative risk of developing Crohn's disease is 2-4× higher in carriers of one mutation (i.e., heterozygotes) and up to 17× higher in carriers of two mutations (i.e. homozygotes or compound heterozygotes). Mutations in the NOD2/CARD15 gene occur in approximately 7-20% of the healthy population and 30-50% of Crohn's disease patients.

Gene, specification: NOD2/CARD15 gene (c.2104C>T, c.2722G>C, c.3019_3020insC)

Type of material to be examined: blood

Indicating specialists: medical genetics

The disease mainly affects the skeletal, ocular, and cardiovascular systems. Patients with Marfan syndrome typically have a very tall stature, long slender limbs, and fingers (positive thumb and wrist signs), joint hypermobility and hypotonic musculature, chest deformities and eye lens dislocation. These patients are mainly at risk of cardiovascular complications - valve defects and aortic dissection. Molecular genetic analysis is used to confirm the diagnosis of suspected Marfan syndrome and to establish comprehensive medical care for the patient.

Gene, specification: Gen FBN1

Type of material to be examined: blood

Indicating specialists: medical genetics

Thus, mutations in the DHCR7 gene lead to reduced cholesterol levels and increased levels of cholesterol precursors. The clinical picture is variable with varying degrees of severity. Patients with this disease very often have growth retardation, intellectual disability, cleft palate, syndactyly of the 2nd and 3rd fingers, microcephaly and facial stigmatization, developmental defects of the heart, kidneys and genitalia in boys. The accumulation of cholesterol precursor is, among other things, embryotoxic and can lead to intrauterine fetal death. Genetic analysis is used to confirm the diagnosis when this syndrome is suspected.

Gene, specification: DHCR7 gene (selected pathogenic variants)

Type of material to be examined: peripheral blood, chorionic villi, amniotic fluid, fetal blood, product of conception (tissue from abortion)

Indicating specialists: medical genetics

Primary genetic diagnoses should also be considered in the differential diagnostic process of a small stature. It is a very heterogeneous group. Relatively common genetic causes include Turner syndrome in girls, or isolated growth retardation due to mutations in the SHOXgene, which can be present in both sexes. Growth failure is also a non-specific symptom of a number of genetic syndromes: chromosomal aberrations, microdeletion syndromes, chromosomal instability syndromes, bone dysplasia and others.

Gene, specification: SHOX gene

Type of material to be examined: blood

Indicating specialists: medical genetics

This technology now allows standard testing of a specific group of genes in the so-called panel of genes whose disorders are associated with hereditary human diseases (e.g. rare disorders such as osteogenesis imperfecta, recessive forms, enchondromatosis, Ollier type, surfactant dysfunction, COFS syndrome, hereditary cancer, metabolic disorders and others). This approach provides a more comprehensive outcome for the patient and allows us to provide adequate care to improve the quality of life. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families and the development of a preventive and therapeutic strategy based on this knowledge.

What is the clinical exome
The clinical exome is an accessible panel of more than 4,500 genes. The genes were selected by experts based on information from the HGMD, OMIM and ClinVar databases.
Who is the clinical exome sequencing for
For the diagnosis of rare hereditary diseases or diseases with a significantly heterogeneous genetic component.
Examination conditions
Examination by clinical exome sequencing is performed only after consultation with a clinical geneticist.

Gene, specification: 4,504 selected genes

Type of material to be examined: blood

Indicating specialists: medical genetics