The effective implementation of whole-exome sequencing- and whole-genome sequencing-based diagnostics in the management of children affected with genetic diseases and the rapid decrease in the cost of next-generation sequencing (NGS) enables the expansion of this method to newborn genetic screening programs. Such NGS-based screening greatly increases the number of diseases that can be detected compared to conventional newborn screening, as the latter is aimed at early detection of a limited number of inborn diseases. Moreover, genetic testing provides new possibilities for family members of the proband, as many variants responsible for adult-onset conditions are inherited from the parents. However, the idea of NGS-based screening in healthy children raises issues of medical and ethical integrity as well as technical questions, including interpretation of the observed variants. Pilot studies have shown that both parents and medical professionals have moved forward and are enthused about these new possibilities. However, either the number of participants or the number of genes studied in previous investigations thus far has been limited to a few hundred, restricting the scope of potential findings. Our current study (NCT05325749) includes 7,000 apparently healthy infants born at our center between February 2021 and May 2023, who were screened for pathogenic variants in 2,350 genes. Clinically significant variants associated with early-onset diseases that can be treated, prevented, or where symptoms can be alleviated with timely introduced symptomatic therapy, were observed in 0.9% of phenotypically normal infants, 2.1% of the screened newborns were found to carry variants associated with reduced penetrance or monogenic diseases of adult-onset and/or variable expressivity, and 0.3% had chromosomal abnormalities. Here, we report our results and address questions regarding the interpretation of variants in newborns who were presumed to be healthy.

Abstract The effective implementation of WES and WGS-based diagnostics in the management of children afflicted with genetic diseases and the rapid decrease in the cost of NGS makes the idea of newborn genetic screening very appealing. Such NGS-based screening greatly increases the number of diseases that can be detected compared to conventional newborn screening, as the latter being aimed at early detection of a limited number of inborn diseases. Moreover, genetic testing provides new possibilities for family members of the proband, as many variants responsible for adult-onset conditions are inherited from the parents. However, the idea of NGS-based screening in healthy children raises issues of medical and ethical integrity as well as technical questions including interpretation of the revealed variants. A few pilot studies have shown that both parents and medical professionals have moved forward and are enthused about these new possibilities. However, the number of participants in studies so far has been limited to a few hundreds, which greatly restricts the scope of potential findings. Our current study includes over 7,000 infants born at our center between February 2021 and May 2023. Clinically significant variants that cause treatable or preventable disorders were observed in 0.9% of inconspicuous infants, 2.1% of the screened newborns being found to carry variants associated with monogenic diseases with incomplete penetrance or late onset and 0.3% having chromosomal abnormalities. Here we report our results and address questions regarding interpretation of variants in newborns who were presumed to be healthy.

Представлено клиническое наблюдение, иллюстрирующее сложность выбора тактики ведения беременности при выявлении участка дупликации хромосомы Х на этапе пренатальной диагностики. Хромосомная перестройка 46,ХХ,dup(X)(q13.3q21.1) диагностирована при молекулярном кариотипировании околоплодных вод у плода женского пола с особенностями фенотипа: полидактилией левой кисти, полидактилией правой кисти под сомнением, гиперэхогенном кишечнике. We presented a clinical case report about the complexity of the choice of pregnancy management when identifying the X-chromosome duplication using prenatal diagnostic methods. Thus, a chromosomal rearrangement dup(X)(q13.3q21.1) was diagnosed by molecular karyotyping of amniotic fluid in a female fetus with phenotype features: left hand polydactyly, right hand polydactyly in question, hyperechoic intestine.

Используемый в настоящее время в России пренатальный скрининг хромосомной патологии основан на косвенных маркерах и имеет ограничение по чувствительности и специфичности. Поэтому более перспективным является применение неинвазивного пренатального ДНК-скрининга анеуплоидий (НИПС). Целью данной работы являлась оценка возможности применения полногеномного НИПС при оказании акушерско-гинекологической помощи. Проведена валидация ДНК-скрининга на образцах с известными результатами пренатальной инвазивной диагностики (N=1134). Доказана возможность транспортировки и хранения образцов (N=477). Проведено отсроченное исследование аликвот плазмы через год после первоначального исследования (N=70). Оценены факторы, которые могут влиять на результаты НИПС - доля плодовой ДНК, индекс массы тела (ИМТ), срок беременности, мозаицизм и другие. Widely performed in Russia prenatally first-trimester screening is based on secondary markers of pathology and has limited sensitivity and specificity. The most promising alternative is the use of noninvasive prenatal screening for fetal aneuploidy (NIPS). This study aims to validate the possibility of NIPS usage for obstetric and gynecological care. DNA screening was validated on samples with known results of invasive prenatal diagnostics (N=1134). It was proven that it is possible to store and transport the samples (N=477). We studied plasma aliquot samples after one year of storage (N=70). Factors that can influence the NIPS results were also evaluated: the proportion of fetal DNA, body mass index (BMI), gestational age, mosaicism, and others.

The article presents our experience with the method of array comparative genomic hybridization (aCGH) during examining fetuses with increasing of the nuchal translucency and normal karyotype in the I trimester of pregnancy. On the basis of recommended algorithms pathogenic and likely pathogenic copy number variation (CNV) were identified in 8.3% cases. One CNV was presented as a rare 13q deletion syndrome. Pregnancy with this syndrome was terminated due to association with severe malformations of the fetus. CGH method can be applied an as essential complement to standard cytogenetic methods or its alternative in some cases.

It was defined that in the first period of fetus gestation, for a child wih a high risk of chromosome disorder, there should be an examination of fetus kariotype. And it has to be done before the second period of fetus gestation nithout delay. In case, if status examination bas not been conducted during the first period of fetus gestation, than it is recommended to be done in the second period of fetus gestation

Fetal blood was collected in 83 women, 71 of these before abortions and in 12 of them with diagnostic purpose. Cardiocentesis was used in 31 cases, cordocentesis in 52. Obstetrical situation was analyzed and fetal heart beat recorded during the procedure. Blood group and rhesus appurtenance were determined in blood samples, Kleinhauer-Batke test was carried out, karyotype, HLA phenotype, and DNA analyzed. A positive result was found dependent on the adequate assessment of an obstetrical situation during fetal blood collection, as well as on equipment resolution power and physicians' experience. The possibility of practical use of cordo- and cardiocentesis is discussed with due consideration for these factors.

The paper presents different ways of preventing the perinatal morbidity and mortality due to genetically predisposed abnormalities, such as environmental protection; definition of the factors having a mutagenic influence on the female; family planning, medico-genetic advisory. It also outlines the methods of perinatal diagnosis, which is now the most effective tool for birth prophylaxis of a baby with a hereditary abnormality.

For the prenatal diagnosis of the fetal status, amniocentesis was performed in 9-12-week pregnancy in 31 females at risk for birth of a baby with chromosomal abnormalities and congenital malformations of the central nervous system. There were no difficulties in carrying out the procedure. A balanced translocation-bearing female was found to have a fetal chromosomal abnormality. Her pregnancy was interrupted at the 11th week; the prenatal diagnosis was evidenced by cytogenetic examination of the abortion specimen. The amniotic fluid alpha-fetoprotein estimated by radioimmunoassay ranged from 15-18 to 550-620 ng/ml. The findings suggest that early amniocentesis may be useful in the prenatal diagnosis of the fetal status and further evidence should be accumulated.

Potentials of the most common chorionic sampling methods have been examined: transcervical biopsy (TCB) (n-65), transcervical aspiration (TCA) (n-63) and transabdominal aspiration (TAA) (n-10). These procedures were done in outpatient settings at 6-12 week's gestation with sonographic guidance using accepted methodologies. TCB and TCA yielded 14.3 mg and 27.5 mg of a sample, respectively. The chorionic sample obtained with TAA was at best 3 mg. The incidence of successful chorionic sampling was 92.4% for TCB, 76.1% for TCA and 80.0% for TAA. Spontaneous abortions occurred after TAA (7.9%) and combined transcervical procedures (10%). These results suggest a potential of TCB and TCA in first-trimester prenatal diagnosis, but TCB has a number of advantages. TAA is a promising technique which, however, requires further sophistication.

Methods of morphologic prenatal diagnosis permit optimizing the medicogenetic prognosis thus preventing the birth of patients with severe incurable forms of congenital bullous epidermolysis and preserve normal pregnancy in risk-group females. Studies on the estimation of the prognostic and prophylactic value of methods for the prenatal diagnosis of congenital dermatoses are necessary.

Late abortions have been induced for genetic indications in 96 women using intra-amniotic administration of 20% sodium chloride or Enzaprost. The results were compared within this group and with a control group of 90 women whose pregnancies were terminated for other indications at similar dates and with the same agents. The use of 20% sodium chloride was associated with significantly higher blood loss and greater lengths of abortions. Patterns and rates of complications were comparable in both groups. These data suggest a utility of 20% sodium chloride and, especially Enzaprost, in late pregnancy termination for genetic indications.

The incidence of extragenital and gynecologic diseases, surgical procedures and menstrual, gestational and family histories have been evaluated in 50 female carriers of balanced chromosomal rearrangements (index group) and 33 women without karyotype abnormalities (control group). This study provided criteria for karyotype testing in women. Counseling guidelines were recommended for female carriage of chromosomal anomalies. These recommendations depend on karyotypic presentations of the anomalies in a carrier: alternatives are prenatal diagnosis of the fetal karyotype and adequate contraception (in robertsonian translocation involving homologous chromosomes).

Threatened abortion, a history of operation or tumor-like masses of the uterus and adnexa were seen in 70 women who underwent amniocentesis or chorionic villus sampling for prenatal diagnosis. A control group comprised 40 women with similar obstetric risks who refused to have the invasive studies done. Evidence has been obtained to indicate that, with certain provisions, amniocentesis and chorionic villus sampling may be employed in situations which are regarded as contraindications.

Twenty-two control women and 5 women at risk for delivering a baby with Brocq's ichthyosiform erythroderma or fatal epidermolysis bullosa were investigated in order to make prenatal diagnosis of inherited fetal skin diseases. Fetal skin abnormalities were detected in 3 of the 5 high-risk patients, and their pregnancies were terminated. There was a spontaneous abortion with a normal fetus in 1 case. In one woman, pregnancy progressed to term delivery of a normal girl. Methodologic aspects of obtaining fetal skin samples and the results of their morphologic studies are discussed.