KARYOTYPE PLUS FETALDNA
Karyotype Plus FetalDNA is the highest non-invasive test of free circulating fetal DNA (NIPT) available today, with the exception of the Total Screen FetalDNA.
It adds, to all the surveys present on Basic FetalDNA and Karyotype FetalDNA, also the screening of a large number of small chromosomal alterations determined by structural rearrangements (which are called microduplications/microdeletions) to a resolution of approximately 10 Mb (for lower resolutions do not get diagnoses on maternal blood but you should only resort to invasive prenatal diagnosis, Amniocentesis or CVS test, carrying out a specific study with microarrays). The Karyotype Plus Fetal DNA, performs the screening of fetal chromosomal aneuploidies related to autosomes 18 21 13 and X, Y sex chromosomes, including fetal sex which, on request, can be omitted.
As specified for the Karyotype FetalDNA test, this is a screening that investigates not only fetal chromosomal aneuploidies related to autosomes 21, 18, 13 and X, Y sex chromosomes, but also leads to the examination all the other chromosomes as happens in the study of the classic Fetal Karyotype. Obviously it also determines fetal sex which, on request, can be omitted.
Every individual has 2 copies of each chromosome and the term aneuploidies refers to numerical anomalies of the chromosomes. The term TRISOMY means that, for that particular chromosome, 3 copies, rather than 2, of that chromosome are observed. The term MONOSOMY means that, for that particular chromosome, 1 copies, rather than 2, of that chromosome are observed. The aneuploidies studied by FetalDNA are the most important and common that can affect the fetus.
TRISOMY OF CHROMOSOME 21 is the most common aneuploidy and refers to the presence of an extra copy of chromosome 21.
This syndrome is known as Down syndrome and represents, with an incidence of about 1/650 births, the most common form of mental retardation (intellectual disability?).
TRISOMY OF CHROMOSOME 18 is the second most common aneuploidy and refers to the presence of an extra copy of chromosome 18. This syndrome is known as Edwards syndrome and is associated with a high abortion risks. Its incidence is estimated to be present in about 1/5000 births.
TRISOMY OF CHROMOSOME 13 is caused by an extra copy of chromosome 13 and is also known as Patau syndrome. It is associated with a high abortion; Newborns have
different pathological conditions that often cause deaths in childhood. It is estimated to have an incidence of about 1/16000 births.
SEX CHROMOSOME ANEUPLOIDIES are anomalies affecting the XY sex chromosomes and which can cause difficulties of language, motor and/or learning in the affected newborns. The most common of this class of aneuploidies is TURNER SYNDROME or X-LINKED MONOSOMY that affects women with only one copy of the X chromosome and has an incidence of about 1/2700 births. Other aneuploidies found with FetalDNA are X-chromosome trisomy (XXX), Klinefelter syndrome, and Jacobs syndrome.
And also, as already mentioned, thanks to the particular elaborate bioinformatics evaluation, it goes to explore ALL THE OTHER ANEUPLOIDIES OF ALL THE OTHER CHROMOSOMES also inspecting the internal structure with definition in the order of megabases.
Karyotype Plus FetalDNA also manages to broaden the investigation of pathologies with a screening that allows to obtain information on the presence of the most important microdeletion syndromes in the fetus. The term microdeletion/microduplication refers to anomalies characterized by the absence of a small chromosomal tract with consequent loss of gene information (microdeletions) or by the addition of supernumerary genomic material (microduplications). Both conditions cause pathologies with complex and variable clinical and phenotypic conditions dependent on the chromosome involved, from the affected chromosome region and the size of the microdeletion itself.
The main microdeletion syndromes investigated are listed below:
DiGeorge Syndrome (22q 11.2 deletion) is due to the loss (deletion) of a portion of chromosome 22. Children affected by DiGeorge syndrome may show incomplete development of the thymus and the parathyroid glands, congenital heart defects and facial anomalies. It has an incidence of about 1/3500 live births.
Cri-du-chat syndrome (5p deletion) is due to deletion of a more or less extensive region of the short arm of chromosome 5. It is characterized by psychomotor retardation, microcephaly, facial anomalies and the emission of a very typical cry (similar to a cat’s meowing) during early childhood. It is estimated to have an incidence ranging from about 1/15000 to 1/50000 live births.
Prader-Willi syndrome (15Q11-q13) is a very heterogeneous pathology determined by deletions on chromosome 15. It is characterized by hypothalamic-pituitary anomalies associated with severe hypotonia during the neonatal period and in the first two years of life behavioral disorders associated with severe mental retardation and delayed psychomotor development. It has an incidence of about 1/25,000 live births.
Wolf-Hirschhorn syndrome is due to a deletion of the short arm of chromosome 4 (region 4p 16.3). The prevalence is 1:50,000 births and is more often affected by females respect to males (2:1) There is marked delay of prenatal growth, constant slowness in the gain of postnatal weight, a typical facies to “Greek warrior helmet” (root of the broad nose that Continues on the forehead) much more evident before puberty, microcephaly and other facial anomalies. Skeletal anomalies, such as kyphosis or scoliosis with malformation of the vertebral bodies, fused or accessories ribs, clubfoot and cleft hands, are present. Hypotonia with muscular hypoplasia, which may be associated with eating problems and contribute to growth retardation, is present. Developmental delay is seriuos.
Jacobsen syndrome which results in multiple congenital anomalies/mental retardation, and is caused by partial deletion of the long arm of chromosome 11. The prevalence is estimated at about 1/100000 births, with a female/male ratio of 2:1. The most common clinical features are pre and post natal growth retardation, psychomotor retardation and characteristic facial dysmorphism.
1p36 deletion syndrome caused by deletion of the distal part of the short arm of chromosome 1. Features characteristic facial dysmorphism, hypotonia, developmental delay, intellectual disability, convulsions, heart disease, hearing loss and prenatal growth retardation is considered to be one of the most common chromosomal deletion syndromes, with incidence of 1/5,000-10,000 live births.
Angelman syndrome is a neurological disorder of genetic origin characterized by severe mental retardation and characteristic facial dysmorphism. Its prevalence is estimated at between 1/10000 and 1/20,000. Patients appear normal at birth. Eating problems and hypotonia may occur in the first 6 months of life, followed by developmental delay between 6 months and 2 years. Typically, the symptoms characteristic of AS occur from the first year of life, with severe mental retardation, absence of language, rice crises associated with stereotyped hand movements, microcephaly, macrostomy, maxillary hypoplasia, prognathism and Neurological disorders with a ‘puppet’ gait.
Langer-Giedion syndrome is caused by the microdeletion of chromosome 8q 23.3-Q 24.13, which leads to the loss of at least two genes: TRPS1 and EXT1. This syndrome is characterized by mental retardation associated with various anomalies, including redundant skin, multiple cartilage exostoses, characteristic facies, and Phalangeal cone-shaped epiphyses. The severity and number of these anomalies vary in different patients.
Koolen-de Vries syndrome the 17q 21.31 monosomy (17q 21.31 microdeletion syndrome) is a chromosomal anomaly characterized by developmental delay, hypotonia in childhood, facial dysmorphism, and friendly/lovable behaviour. The prevalence of the syndrome is estimated at about 1/16,000. Facial dysmorphism is characterized by a high and broad forehead, elongated facies, upward-facing palpebral fissures, epicanthus, abnormal shape of the nose (tubular or pear-shaped), globular nose tip, large and prominent ears and everted lower lip. Abnormalities of pigmentation and hair texture are frequent.
Hereditary neuropathy with liability to pressure palsy (HNPP) is a hereditary disease of peripheral nerves with recurrent mononeuropathy, usually caused by mild physical activity. In rare cases, HNPP may begin with a brachial plexopathy with paralysis and unilateral painful sensory loss of the arm. Small anomalies in the function of cranial nerves are seldom observed. In some cases, deep tendon reflexes are missing and hollow foot (Pes Cavus) are present. The phenotype of HNPP often evolves into a symmetrical sensorimotor polyneuropathy in elderly patients.
Deletion syndrome 18q people with the proximal deletion of the long arm of chromosome 18, have an intact chromosome 18, but the other is missing a part of variable size that can affect their learning and physical development. Most of the clinical difficulties are probably caused by the presence of a single copy (instead of two) of a certain number of genes. However, the other genes of the child and his personality help him to determine his future development, needs and abilities.
Alagille syndrome (AGS) is characterized by chronic cholestasis with poor interlobular bile ducts, peripheral pulmonary artery stenosis, vertebral segment anomalies, characteristic facies, posterior embryotoxon/anterior segment anomalies, retinitis pigmentosa and renal dysplasia. The estimated prevalence is about 1/70,000. In newborns the disease may occur associated with prolonged jaundice with hyperbilirubinemia and/or cardiac signs and symptoms. Cardiac anomalies include atresia or pulmonic stenosis, atrial and/or ventricular septal defects, tetralogy of Fallot, Patent Ductus Arteriosus. Ophthalmic abnormalities include posterior embryotoxon (75% of cases), retinitis pigmentosa, pupillary abnormalities, and optic disc. In some cases there is a delay in growth and development and fat malabsorption (rickets can occur) are observed. Renal dysplasia is possible.
Rubinstein-Taybi syndrome is a rare but very severe malformation syndrome characterized by congenital anomalies (microcephaly, characteristic facies, broad thumbs and toes, and postnatal growth retardation), short stature, cognitive disability and behavioral disorders.
WAGR syndrome is an acronym for Wilms tumor Syndrome – aniridia – genitourinary anomalies – mental retardation. Wilms tumor or Nephroblastoma is the most frequent renal cell carcinoma in children, responsible for 6-8% of childhood cancers. About 1% of these tumors are associated with aniridia. The prevalence of WAGR syndrome is less than 1 on 100,000 births. The syndrome is associated with an increased risk of Wilms tumor, which can be highlighted at any age, and with total or partial aniridia, with possible glaucoma or cataract, genitourinary disorders, ranging from sexual ambiguity to ectopic testis and variable mental retardation. Atypical ocular signs such as bilateral microphthalmia, corneal anomalies, and agenesis of the left anterior chamber with retinal dysfunction have been reported In a child.
Potocki-Shaffer syndrome is characterized by multiple exostoses, parietal perforations, large anterior fontanel and, occasionally, intellectual disability and small craniofacial dysmorphism. The syndrome is caused by a deletion of contiguous genes on the short arm of chromosome 11p 11.2.
Miller-Dieker syndrome or lissencephaly type 1 from LIS 1 anomalies or Miller-Dieker syndrome (MDS) is a syndrome for deletion of contiguous genes on chromosome 17p 13.3, characterized by classical lissencephaly (smooth brain, with poor cerebral convolution ) and characteristic facial signs. Other congenital malformations may be part of this condition. Children with MDS have severe growth retardation, usually associated with epilepsy and eating disorders. In almost 100% of patients, visible or submicroscopic deletions of the 17p 13.3 region involving the LIS1 gene are present.
1q 21.1 Deletion syndrome is a recently described recurrent disease, characterized by a variable clinical picture, different from that observed in the Thrombocytopenia-absent radius (TAR) syndrome. The clinical phenotype is extremely variable; The most common, but inconstant, signs are microcephaly, developmental delay or small intellectual disability, facial dysmorphism, however poorly marked, and ocular anomalies. Congenital malformations are not common. Autism spectrum disorders, schizophrenia or attention deficit hyperactivity disorder are rarely reported.
Kleefstra syndrome (KS) is a genetic disorder characterized by intellectual disability, childhood hypotonia, severe expressive language disorder and characteristic facies, associated with a series of additional clinical signs.
Phelan-Mcdermid syndrome 22q13 monosomy syndrome (22q 13.3 deletion syndrome or Phelan-Mcdermid syndrome) is a chromosomal microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, accelerated or normal growth, absent or delayed speech development and dysmorphism. The syndrome is underdiagnosed and its actual incidence is not yet known. Common clinical features include long eyelashes, large or dysmorphic ears, relatively large hands, dysplastic toenails, bushy eyebrows, dolicocephaly, full cheeks, globose nose, and pointy chin. The behavior is autistic-like with decreased perception of pain and frequent chewing and mouth movements.
Smith-Magenis syndrome SMS is a sporadic 17p 11.2 deletion disorder of the RAI1 gene (retinoic acid-induced 1; 90%) or by mutation of the gene itself (10%). Recognizable clinical picture includes craniofacial signs (brachycephaly, convex forehead, hypertelorism, synophrys, upward oblique palpebral fissures, mid- face hypoplasia, large square face with depressed nasal bridge, reversed upper lip to “curtain”, neonatal micrognathia), other skeletal anomalies. The world prevalence is 1/15,000 to 25,000 in all ethnic groups, but is likely to be underdiagnosed.
NB: It is reiterated that the above mentioned microdeletions will only be screened without any diagnostic certainty. In fact these diagnoses ARE NOT OBJECTIVELY POSSIBLE WITH ANY EXISTING NIPT. Their execution is not yet approved and recognized by the scientific societies and by the national and international Guidelines, it must be considered only for scientific research and has no clinical value. However, in our tests, this research was scientifically reliable. It reiterates once again that, for confirmation or exclusion, reference should only be made to invasive tests using microarrays technique on fetal material taken through Amniocentesis or CVS Test.
The Karyotype Plus FetalDNA also includes, for free, the search for the most frequent mutations in maternal CYSTIC FIBROSIS. In this way, if one of these mutations is present in the mother, it will be necessary to investigate whether the fetus is also a simple carrier or, if the father is also a carrier, he ran the risk of being affected by cystic fibrosis. This occurs in 25% of cases if both parents were healthy carriers.
Cystic fibrosis (FC) is an hereditary disease with autosomal recessive transmission, i.e. it is inherited from both parents carrying an altered gene. For this genetic error an alteration of the mucus of the various organs is determined. The organs frequently affected are the liver, intestine, reproductive system and lungs where the particularly dense mucus leads to serious respiratory problems and consequent infections.
With the Karyotype Plus FetalDNA the analysis of the maternal gene is carried out through a screening called level 1 that allows to analyze the most common and frequent mutations managing to identify about 83% of the carriers. In the Italian population the estimated frequency of the healthy carriers (often unaware of it) is 1 in 25 – 30, that of the affected born is 1 on 2500 – 3000.
NB: The mutations analyzed are exclusively the following: 711+1G-T, 621+1G-T, 1717-1G-A, 3849+10kbC-T, 2789+5G-A, G542X, G85E, G551D, R553X, N1303K, R117H, R1162X, L1077P, L1065P, W1282X, R347P, I507del, T338I, F508del, 1677delTA, 2183AA-G, S549R, Q552X, 852del22, R1066H, G1244E, 1259insA, D1152H, 711+5G-A, R1158X, 4382delA, 4016insT, A455E, 1706del17, I502T, 3199del6, S912X.
If the mother has the negative Rhesus factor (documentable and visible at the time of the FetalDNA request), it is possible to request for free the analysis of the fetal Rhesus.
If you do not want to know the sex of the fetus you can make that choice.
N.B. Although FetalDNA tests provide maximum diagnostic accuracy today achievable with maternal blood screening methodologies, as is clear in the informed consent, no prenatal non-invasive testing (NIPT), regardless of Methodology and the company that produces and markets it, provides, according to the current Guidelines, the insights related to the screening of sex chromosomes, all the other chromosomes, microdeletions/microduplications and fetal monogenic diseases.
It is therefore correct to inform that no widespread and commercialized NIPT tests can guarantee a sufficient degree of accuracy in relation to the genetic problems mentioned above. To this end, it reiterates once again the existence of sufficient scientific guarantees that can validate the clinical use of information related to the search for pathologies of sex chromosomes, of the other 22 autosomes, of microdeletions/ Microduplications and fetal monogenic diseases.
Therefore, subject to such research, the pregnant woman must be aware that all scientific literature and national and international Guidelines stipulate that only prenatal invasive diagnosis (Amniocentesis or CVS Test) represents the diagnostic test for such investigation
To compare the various NIPT tests available go to: www.fetaldna.it/en/fetal-dna
or explore the table below: