-LOW RISK of the chromosomal disease
The risk of the fetus having Down, Edwards, Patau, Turner, or DiGeorge syndrome is very low. Abnormalities in other chromosomes were also not detected. Since NIPTIFY is not a diagnostic test, false-negative or false-positive results are still possible. The NIPTIFY test cannot detect chromosomal mosaicism or rare monogenic diseases. In addition, a low chromosomal risk score does not indicate other abnormalities in fetal development detected by ultrasound (for example, brain or heart malformations, spinal malformations, or developmental disorders).
-HIGH RISK of the chromosomal disease
The fetus has a high risk for Down, Edwards, Patau, Turner, DiGeorge, or other incidental findings. An incidental finding can be a microdeletion or an incorrect copy number of any other chromosome, including sex chromosomes. As the NIPTIFY is a screening test, the pregnancy should not be terminated based on this result only. An invasive diagnostic test such as amniocentesis should be considered to confirm the high risk of chromosomal disease. In case of a high-risk incidental finding, the doctor or a medical geneticist will decide the necessity for follow-up analysis.
-FETAL SEX
NIPTIFY detects fetal chromosomal sex based on DNA. If a Y-chromosome is detected in the maternal blood, there is a boy. If there are no signs of a Y-chromosome, there is a girl. In rare cases (<0.2%), the fetal chromosomal sex can not be reliably determined. The reason for such cases can be a vanishing twin, where a girl fetus is in good shape, but the deceased boy’s fetal Y-chromosome traces are still detectable in the mother's blood.
-The risk of chromosomal disease cannot be determined
The chromosomal disease risk assessment failed. The result does not mean any elevated risks. A technical failure in blood sample transportation or laboratory processes may cause the failure. In case of a non-informative result, the NIPTIFY laboratory provides a retest for the patient. One retest is free for the patient.
Incidental findings
- Clinically significant microdeletions and microduplications
- Sex chromosome aneuploidies
- Trisomy in autosomes except 13, 18 and 21
- Monosomy in all autosomes
- Partial DNA copy number change (more than 30 million DNA base pairs) in chromosomes 13, 18, 21 and X
Incidental findings can significantly affect maternal or fetal health and the functioning of the placenta until the end of pregnancy. Every incidental finding requires an individual approach and counseling. In rare cases, NIPTIFY can detect maternal chromosomal anomalies, which can indicate an existence of a tumor.
There is a high probability that the reported incidental finding occurs only in the placenta, and the fetus is healthy. In those cases, it only affects the course of pregnancy. For example, placental trisomy 16 can be accompanied by a developmental disorder of the placenta, which can lead to fetal growth restriction. Such pregnancies must be monitored more thoroughly to minimize the health risks for the mother and the fetus. If trisomy 16 is confirmed by a diagnostic test (amniocentesis) in a fetus, the pregnancy will likely end with a miscarriage.
If an incidental finding occurs in clinically relevant microdeletion regions, it is recommended to confirm the result by DNA-based diagnostic analysis (amniocentesis).
-Down syndrome
It is caused by three copies of chromosome 21 instead of the usual two copies. The prevalence varies from 1/400 to 1/3,000 live births [1]. Characterized by variable intellectual disability, characteristic morphological features, short stature, weak muscle tone (hypotonia), loose joints, and increased risks of some medical complications all-life-long (for example, hearing and vision problems, heart defects, digestive malformations, earlier aging and early-onset Alzheimer disease) [1][2][3].
-Edwards syndrome
A third copy of chromosome 18 causes it. Incidence is estimated at between 1/6000 and 1/8000 births [3]. Affected individuals have growth delay and abnormalities of organs that develop before birth, including heart defects, breathing abnormalities, digestive tract defects, malformations of kidneys and urinary tract. Due to several life-threatening medical problems, many individuals with trisomy 18 die before birth or within their first month. 5 - 10% of children with this condition live past their first year, and these children often have a severe intellectual disability. [4][5][6]
-Patau syndrome
A third copy of chromosome 13 causes it. Its incidence is estimated at between 1/8,000 and 1/15,000 births [7]. It is associated with severe intellectual disability and physical abnormalities in many body parts. Affected individuals often have heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes, extra fingers or toes, an opening in the lip, an opening in the roof of the mouth, and weak muscle tone (hypotonia). [8][9] Half of the infants die within the first month of life, and 90% die before one year of age from cardiac, renal, or neurologic complications [7].
-DiGeorge syndrome
It is caused by a small deletion of the long arm on chromosome 22 (22q11.2). The prevalence at birth is estimated at 1/4,500 to 1/10,000 [10]. Syndrome has a variable clinical phenotype that can range from mild to severe. Typically characterized by cardiac defects, the roof of the mouth anomalies that may lead to hypernasal speech and feeding difficulties, facial dysmorphism, developmental delay, and immune deficiency.[10][11][12] The prognosis depends on the severity of the disease. The infant mortality rate is relatively low; in adults, mortality is higher than that of the rest of the adult population.[10] Less than 1% of patients with 22q11.2 microdeletion have the severe subtype of DiGeorge syndrome with a poor prognosis [12].
-Turner syndrome
Sex chromosome anomaly where females have only one normal X chromosome instead of two (45,X). The condition occurs in about 1/2,500 female births [13]. Phenotype is variable and can differ from one person to another. Common symptoms are short stature and early loss of ovarian function, which can fail to attain puberty. Most affected women are infertile [14]. One-third to one-half of individuals are born with a heart defect [15]. Other features can be extra skin on the neck, swelling (lymphedema) of the hands and feet, skeletal abnormalities, and kidney problems. Intelligence is usually normal, but affected individuals may experience developmental delays, learning disabilities, and/or behavior problems [14][15][16].
-Klinefelter syndrome
Sex chromosome anomaly where males receive two X chromosomes instead of one (47,XXY). The estimated prevalence is between 1/500 to 1/1,000 males [17]. Signs and symptoms are variable, and the condition often isn't diagnosed until adulthood or may never be diagnosed [18]. The most common symptom is infertility. Affected males may have tall stature and abnormal body proportions. They typically have small testes and produce reduced testosterone, leading to delayed or incomplete puberty, breast enlargement, decreased muscle mass and bone density, and diminished facial and body hair. Some affected individuals have undescended testes, the opening of the urethra on the underside of the penis, or a tiny penis. Affected boys may have learning disabilities and developmental delays. [19][20]
-Jacobs syndrome
Sex chromosome anomaly where males receive two Y chromosomes instead of one (47,XYY). It occurs in approximately 1 out of 1,000 newborn males. Patient presentations may vary, and many patients have few or no phenotypic abnormalities. Many affected individuals are never diagnosed or not diagnosed until later in life. Condition is associated with tall stature and can include large head, large teeth, flat feet, fifth fingers that curve inward (clinodactyly), widely spaced eyes, and abnormal curvature of the spine (scoliosis). They may have an increased risk of asthma, seizure disorders, autism spectrum disorder, learning disabilities, and behavioral problems. Fertility problems are slightly increased compared to the general population; however, in most cases, fertility is normal. [21][22][23]
-Trisomy X
Sex chromosome anomaly in females is caused by a three X chromosomes instead of two (47,XXX). The occurrence is approximately 1 in 1,000 female births. It has a variable phenotype, with most individuals only mildly affected or asymptomatic. It is estimated that 10% of individuals with trisomy X are diagnosed [24]. Common features include tall stature, low muscle tone (hypotonia), and abnormal bending of the fifth fingers (clinodactyly). Other associated findings are seizures, kidney problems, developmental delays, and learning disabilities. Sexual development and fertility are usually normal, but some affected females may have fertility problems, abnormal ovaries and/or uterus development, premature ovarian failure, and delayed or early onset of puberty. [25][26]
-Williams-Beuren syndrome
It is caused by a deletion of genetic material from a specific region of the long (q) arm of chromosome 7 (7q11.23). Prevalence is approximately 1/7,500 [27]. It is characterized by developmental delay, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, hypersensitivity to sound, connective tissue abnormalities, growth deficiency, endocrine abnormalities (e.g., hypercalcemia, hypothyroidism), and distinctive facies. The majority of patients suffer from cardiovascular disease. The narrowing of various blood vessels near the heart is common, which can lead to increased blood pressure, arrhythmia, and cardiac failure. Most individuals will require lifelong supervision . [27][28][29][30]
-1p36 deletion syndrome
It is caused by a deletion of genetic material from a specific region in the short (p) arm of chromosome 1. It is believed to affect 1 in 5,000 newborn babies. Higher frequency is observed among females, and the reason is not known [31][32]. The disorder typically causes severe intellectual disability. Most affected individuals have brain structural abnormalities and do not speak or speak only a few words. Typical is a small head and distinctive facial features. Affected individuals may have weak muscle tone, swallowing difficulties, seizures, behavior problems, and abnormalities of the skeleton, heart, gastrointestinal system, kidneys, or genitalia. Patients usually will remain dependent on others and require medical support throughout life. [32][33][34]
-Wolf-Hirschhorn syndrome
It is caused by the deletion of genetic material near the end of the short (p) arm of chromosome 4 (4p16.3). The estimated birth prevalence is 1/20,000 - 50,000. It occurs more frequently in females than males (2:1) [35]. The symptoms of this syndrome vary among affected individuals based on the size and location of the deletion. The major features include a characteristic facial appearance (wide-set eyes, small head), delayed growth and development, intellectual disability (mild to severe), low muscle tone, and seizures. Feeding problems are common and may be quite severe. Other features may include skeletal abnormalities, congenital heart defects, hearing loss, urinary tract malformations, and/or structural brain abnormalities. [36][37][38]
-Jacobsen syndrome
It is caused by a deletion of genetic material at the end of the long (q) arm of chromosome 11 (11q23.3-q25). The estimated incidence is 1 in 100,000 newborns, with a female/male ratio of 2:1 [39]. Signs and symptoms vary among affected people but often include Paris-Trousseau syndrome (a bleeding disorder); distinctive facial features; delayed development of motor skills and speech; and cognitive impairment. Other features include infant feeding difficulties, short stature, behavioral problems, immunodeficiency, and developmental anomalies affecting the heart, kidneys, gastrointestinal tract, genitals, central nervous system, and skeleton. [40][41]
-Cri-du-chat syndrome
It is caused by a partial or total deletion of the short (p) arm of chromosome 5 (5p15.3-15.2). The disease occurs in 1/ 15,000 to 1/50,000 live births [42]. The symptoms vary among individuals. Infants with this condition often have a high-pitched cry that sounds like a cat's. The disorder is characterized by moderate to severe intellectual disability, delayed development, small head size, pre-and postnatal growth delay, and weak muscle tone in infancy. Affected individuals also have distinctive facial features.[43][44] Abnormal side-to-side curvature of the spine (scoliosis) is a frequent complication. Approximately 15-20% of affected infants have congenital heart defects. [44]
-Langer-Giedion syndrome
It is also known as Trichorhinophalangeal syndrome type II, caused by a deletion of genetic material from a specific region in the long arm (q) of chromosome 8 (8q23.3-q24.1). Prevalence is ~1/100,000 [45]. The condition causes bone and joint malformations; distinctive facial features; intellectual disability; and abnormalities of the skin, hair, teeth, sweat glands, and nails. People with this condition have multiple noncancerous (benign) bone tumors called osteochondromas. Affected individuals may develop a few to several hundred osteochondromas. These bone growths typically begin in infancy to early childhood and stop forming around adolescence. Depending on the location of the osteochondromas, they can cause pain, limited range of joint movement, or damage to blood vessels or the spinal cord. [46][47]
-Angelman syndrome
One of the causes is a deletion of a maternally inherited region of the long arm of chromosome 15 (15q11.2-q13.1) [48]. The disorder affects an estimated 1 in 12,000 to 20,000 people. It is associated with delayed development, intellectual disability, severe speech impairment, problems with movement and balance, and happy, excitable demeanor. Most affected children also have recurrent seizures (epilepsy) and a small head size (microcephaly). [49]
-Prader-Willi syndrome
One of the causes is a deletion of the paternally inherited region of the long arm of chromosome 15 (15q11.2-q13.1) [50]. The disorder affects an estimated 1 in 10,000 to 30,000 people. The condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development in infancy. In childhood, affected individuals develop extreme hunger, leading to chronic overeating and obesity. Affected individuals typically have mild to moderate intellectual impairment, distinctive facial features, underdeveloped genitals, and infertility. [51]
-15q11-q13 duplication syndrome
It is caused by duplication of genetic material on a specific region of the long (q) arm of chromosome 15. It is the same region in which deletions are causing Angelman/Prader-Willi syndrome. Prevalence is 1 in 5,000 individuals [52]. Characterized by central hypotonia, developmental delay, intellectual disability, and behavioral difficulties [53]. Speech and language development are particularly affected, with some individuals never developing functional speech. More than half of people with dup15q syndrome have recurrent seizures (epilepsy). [54]
-7q11.23 duplication syndrome
It is caused by a duplication of a region on the long (q) arm of chromosome 7, called the Williams-Beuren syndrome critical region, because its deletion causes a Williams-Beuren syndrome. Prevalence is estimated to be 1 in 7,500 to 20,000 people [55]. The disorder shows a variable phenotype that typically manifests with speech and language delay or disorder, mild to moderate intellectual delay (patients could be in the normal range), and distinctive craniofacial features. Hypotonia, developmental coordination disorders, behavioral problems, and various congenital anomalies can be presented. [56][57] Approximately half of the individuals have enlargement (dilatation) of the aorta [55].
-Duchenne muscular dystrophy
It is caused by changes in the DMD gene on the X chromosome (Xp21.2-p21.1). NIPT screening detects only a minor fraction of Duchenne muscular dystrophy cases (microdeletions). The disease occurs primarily in males, affecting approximately 1 in 3,500 male births. It is characterized by weakness and wasting (atrophy) of the muscles. The disease is progressive, and most affected individuals require a wheelchair by their teenage years. Life-threatening severe complications may develop, including heart muscle disease (cardiomyopathy) and breathing difficulties [58] [59].
-17q12 deletion syndrome
It is the outcome of a deletion of the long (q) arm of chromosome 17. The prevalence range is 1/14,000 to 1/50,000 [60]. Characterized by variable combinations of the following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder) [60][61].
-Smith-Magenis syndrome
It results mainly from deleting a small piece of chromosome 17 short (p) arm (17p11.2). The estimated prevalence is 1/15,000-25,000 [62]. The disorder is characterized by a pattern of abnormalities present at birth (congenital) and behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances, and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary from one individual to another. [63][64]
-Koolen-De Vries syndrome
It is caused mainly by deleting a small part of the long (q) arm of chromosome 17 (17q21.31). The prevalence is 1 in 16,000 to 55,000 [65][66]. The syndrome is associated with a broad spectrum of symptoms that vary from person to person. Frequent features in individuals with this condition include feeding problems in infancy, muscle weakness (hypotonia) in young children, developmental issues, language/speech delay, learning disabilities and mild to moderate intellectual disability, epilepsy (in about 1 in 3 persons), characteristic facial features, visual problems, hearing impairment and/or other congenital abnormalities. [66][67]
-Phelan–McDermid syndrome
It is caused by the deletion or disruption of the segment of the long arm (q) of chromosome 22 (22q13). The estimated prevalence is 1/30,000 live births [68]. Features vary widely and involve many parts of the body. Characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. [69] Individuals with the syndrome tend to have a decreased sensitivity to pain. Many also have a reduced ability to sweat, which can lead to a greater risk of overheating and dehydration. [70]
-15q24 deletion syndrome
It is caused by deleting a small piece of the long (q) arm of chromosome 15. Incidence in the general population is about 1 in 42,000 [71]. It is characterized by growth delay, intellectual disability, and distinct facial features. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. [71][72]
-Neurofibromatosis 1
It is caused by changes in the DMD gene on the X chromosome (Xp21.2-p21.1). NIPT screening detects only a minor fraction of Duchenne muscular dystrophy cases (microdeletions). The disease occurs primarily in males, affecting approximately 1 in 3,500 male births. It is characterized by weakness and wasting (atrophy) of the muscles. The disease is progressive, and most affected individuals require a wheelchair by their teenage years. Life-threatening severe complications may develop, including heart muscle disease (cardiomyopathy) and breathing difficulties [73][74][75].
-3q29 deletion syndrome
It results from deleting a small piece on the long (q) arm of chromosome 3. The approximate prevalence is 1/30 000 to 150 000. The clinical phenotype is variable. Symptoms may include delay reaching developmental milestones such as sitting, walking, talking, feeding difficulties, intellectual disability, increased risk of behavioral or psychiatric disorders, frequent ear, and respiratory infections, and a small head size (microcephaly). Some babies with this condition are born with a cleft lip or cleft palate, and some have been reported to have heart defects. [76][77][78]
-2q31.2 deletion syndrome
It is caused by deleting the specific region of the long (q) arm of chromosome 2. It has been associated with mental retardation, neonatal hypertonia, dysmorphic features, scoliosis, abnormality of fingers and toes, and behavioral problems [79].
-Miller-Dieker syndrome
It is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17 (17p13.3). The condition appears in 1 case per 100 000 live births [80]. Characterized by a specific brain malformation (lissencephaly), distinctive facial features, and severe neurologic abnormalities, including intellectual disability and seizures. Affected individuals may also have life-threatening breathing problems. Significantly few affected children survive beyond childhood. [81][82]
-Pallister-Killian syndrome
It is caused by mosaic tetrasomy for the chromosome 12 short (p) arm, resulting in four copies of the short arm of chromosome 12 instead of the standard two. The estimated prevalence is around 1/20 000 [83]. The signs and symptoms vary in severity. They are characterized by extremely weak muscle tone (hypotonia) in infancy and early childhood, intellectual disability, seizures, distinctive facial features, and other birth defects, e.g., diaphragmatic hernia, anal, and heart defects. Speech is often limited or absent. Affected individuals may require life-long medical care. About half of the patients may not survive childhood. [84][85][86]
-Trisomy 8
If most or all cells have the extra (third) chromosome 8, the condition is known as full or complete trisomy 8. Full trisomy 8 is fatal and often results in miscarriage during the first trimester of pregnancy [87]. Individuals with mosaic trisomy 8 (when some cells have standard two copies of chromosome 8) may be viable. Mosaic trisomy 8 affects 1 in every 25,000 to 50,000 babies. Males are more frequently affected than females [88]. The signs and symptoms vary but may include distinctive facial features; intellectual disability; and joint, kidney, cardiac, and skeletal abnormalities. [89][90]
-Trisomy 9
It is a result of an extra (third) copy of chromosome 9. Full trisomy 9 is nearly always fatal, causing miscarriage in the first trimester. Those who survive usually have mosaic trisomy 9 (some cells have two standard copies of chromosome 9) [91]. Mosaic trisomy 9 has a variable phenotype, principally characterized by intellectual disability, growth and developmental delay, facial dysmorphism, congenital heart defects, and urogenital, skeletal, and central nervous system anomalies. [92][93]
-Trimsomy 16
It happens if chromosome 16 has an extra copy. Full trisomy 16 will likely result in a fetal loss in the first trimester. Those who survive usually have mosaic trisomy 16 (some cells have two standard copies of chromosome 16). The phenotype is variable, and symptoms can include poor growth of the fetus during pregnancy, congenital heart defects, unusual facial features, underdeveloped lungs or respiratory tract problems, musculoskeletal anomalies, and hypospadias (urethral opening too low) in boys. There is also an increased risk of premature birth for infants with trisomy 16 mosaicism. [94][95][96]
-Trisomy 22
It is caused by an extra (third) copy of chromosome 22. Complete trisomy 22 usually causes first-trimester miscarriage [97]. Those who survive typically have mosaic trisomy 22 (some cells have two normal copies of chromosome 22). The phenotype may vary among the patients. The characteristic features typically include prenatal and postnatal growth failure or delay, intellectual disability, asymmetrical development of the two sides of the body (hemidystrophy), congenital heart defects, and other physical abnormalities. [98][99]
Why is NIPTIFY sometimes require retesting?
In rare cases, NIPTIFY Focus Plus cannot determine the risk of chromosomal diseases. Our prognosis shows this occurs in less than 0.1% of all patients after retesting. The reason for such cases is a high standard deviation in the results or low fetal cell-free DNA fraction in maternal blood. A low fetal fraction does not indicate a higher risk of chromosomal disease.
The low fetal DNA fraction can be caused by high maternal body mass index (BMI higher than 30). Premature testing, asymptomatic viral infections, or other biological and technical factors can cause low fetal DNA fraction. Fetal cell-free DNA fraction increases as the pregnancy progress and does not depend on the volume of the blood sample. In case of a low fetal fraction, we recommend giving another blood sample (retest), which is free for the patient.