Microarray and RASopathy-disorder testing in fetuses with increased nuchal translucency.

OBJECTIVES: To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RASopathy-disorder (RD) pathogenic variants in a cohort of pregnancies with nuchal translucency thickness (NT) ≥ 3.5 mm, and to propose a clinical protocol for surveillance of this group of patients. METHODS: This was a retrospective chart review of patients referred to The Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital between January 2013 and December 2015, due to NT ≥ 3.5 mm, who underwent chorionic villus sampling or amniocentesis. Patients underwent extensive genetic counseling prior to invasive procedures and testing. Quantitative fluorescence polymerase chain reaction (QF-PCR) was performed as the first-line test for aneuploidy. If the result was negative, patients underwent karyotyping and/or chromosomal microarray analysis (CMA), and if the findings were normal, they had testing for RD pathogenic variants, which included nine known genes. Patients also underwent detailed fetal ultrasound examinations and echocardiography, performed by expert operators. RESULTS: A total of 226 eligible patients were identified. In 116/226 (51.3%) patients, QF-PCR identified a chromosomal aneuploidy. The remaining 110/226 (48.7%) patients had further genetic testing. Karyotyping/CMA detected an abnormal/pathogenic cytogenetic result in 9/110 (8.2%) patients, as well as five variants of unknown significance (VOUS). RD testing yielded three pathogenic variants (3/103), giving a detection rate of 2.9%, and one VOUS. The optimal NT cut-off for RD screening was 7.9 mm in this population. In 92/110 (83.6%) patients, the genetic investigations were normal. Of these pregnancies, an early (14-16 weeks' gestation) detailed fetal ultrasound examination identified a structural abnormality in 24 (26.1%), 15 (16.3%) had an abnormal detailed ultrasound examination at 18-22 weeks' gestation and fetal echocardiography showed a cardiac abnormality in nine (9.8%). The birth outcome in the 83 pregnancies that had normal genetic investigations and known outcome included seven (8.4%) cases of termination of pregnancy, seven (8.4%) cases of intrauterine fetal death and 69 (83.1%) cases of live birth. Nine (9.8%) patients were lost to follow-up. CONCLUSIONS: Both CMA and molecular testing for RD are important investigations in pregnancies with NT ≥ 3.5 mm. The use of genetic testing combined with fetal ultrasound examination provides valuable information that can influence pregnancy outcome, and provide recurrence risks, in this patient population. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype.

Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway.

Physical development in Tuvinian adolescents.

It was found that mean values of height and mass in 13-14-year-old indigenous Tuvinian children were increased for the last 26 years. We have found gender difference in a chronological dynamics of a yearly body mass and height increases. As for the last ten years, these changes correspond to a harmonic physical development only for the boys of 13. At the same time we observed an insufficient increase in body mass and significant blood pressure increase in senior boys. A yearly percentage of the increase in blood pressure in junior boys was the same as mass increase, but among the senior children the increase in blood pressure was greater compared with mass increase. In the 70-80s, the indices of body mass and height increases for Tuvinian girls and boys were the same.

Psychological health, physical development and autonomic nervous system (ANS) activity in Siberian adolescents.

Cultural and biological influences on psychological health were examined in 256 schoolchildren, aged 13 to 17 years, in Novosibirsk, Russia. Children's competence and problems were assessed using the Youth Self-Report (YSR), the Child Behavior Checklist (CBCL) and the Teacher's Report Form (TRF). Compared with Americans, Siberian children scored lower on competencies and higher on somatic complaints. Height predicted mothers' ratings for children's Total Competence and Delinquent Behaviour and was negatively related to boys' Anxious/Depressed problems. Triceps skinfold thickness predicted children's self-ratings for somatic complaints. In girls, self-ratings for Delinquent Behaviour were related to heart period variability and subscapular skinfold thickness and self-ratings for Attention Problems were related to triceps skinfold thickness. Systolic blood pressure was negatively associated with behavioural problems, thought problems and somatic complaints. Overall, the findings suggest culture-bound and demographic influences on competence and problems in Siberian adolescents and variation related to physical development and autonomic nervous system activity.

[Systemic reactions and the central mechanisms of respiratory regulation in adaptation to cold and hypoxia]. / Sistemnye reaktsii i tsentral'nye mekhanizmy reguliatsii dykhaniia pri adaptatsii k kholodu i gipoksii.

Respiratory and circulatory changes in response to various physiological stimuli (hypoxia, cold, etc.) were studied. The respiratory center was found to play the leading role in the developing a response. Upon repeated exposures to cold and hypoxia, the central regulatory mechanisms include nonspecific compensatory mechanisms by changing the sensitivity of the respiratory center and its thresholds. Various regulatory strategies were found at different stages of adaptive processes. There was a correlation between the changes in the respiratory center and thermoregulatory shifts. The respiratory center was demonstrated to play a system-forming role. It is suggested that determination of the sensitivity of the respiratory center may serve for prognostic and diagnostic purposes.

Elasticity changes in the large arteries of human limbs in response to cycle ergometry performed with upper and lower limbs.

At rest and after cycle ergometry the elastic properties of the large arteries of limbs of healthy men were examined using an original non-invasive quantitative oscillometric method. It has been shown that in response to muscle work performed with the legs there is a decrease of the effective inner radius, and an increase of the characteristic impedance modulus and bulk modulus and of the elastic resistance of the intact and relaxed wall in the large arteries in the upper limbs. All these changes testify to an increase of vascular tension in the upper limbs. In response to work performed with the hands, there is an increase of the effective inner radius of large arteries of the upper limbs, a large increase of the pulsatile blood volume increment of the intact vessels and a decrease of the characteristic impedance modulus, of the bulk modulus and of the elastic resistance of the intact arterial wall. These changes indicate a decrease of the vascular tension of these arteries. In response to work performed either with the legs or with the hands a decrease of the effective inner radius of large arteries and an increase of the elastic resistance of the relaxed arterial wall were observed in the lower limbs, all these changes indicating relatively small changes in tone of these vessels. It is concluded that the wall tension of large arteries supplying blood to the muscles of non-working limbs is increased. Vascular tension changes in the arteries in working limbs are accounted for by the superimposition of centrally originating vasoconstriction with local vasodilatation, which also affects large arteries.

[Noninvasive quantitative determination of the modulus of characteristic impedance of human limb arteries]. / Neinvazivnaia kolichestvennaia otsenka modulia kharakteristicheskogo impedansa arterii konechnostei u cheloveka.

A noninvasive method of quantitative evaluation of characteristic impedance modulus of human limb arteries based on blood pressure and blood vessel volume parameters is described. The differences in the value of characteristic impedance modulus in the upper and lower limb arteries in supine and resting subjects have been shown. Under postural effects the impedance changes in the lower limb arteries are proportional to those of mean blood pressure in these vessels. No significant impedance alterations on effort have been observed in these arteries. The impedance of the upper limb arteries increased in passive orthostatic position and after physical exercises of the lower limbs. Characteristic impedance modulus of these arteries decreased after physical exercises of the upper limbs.

[Elastic properties of the arteries and hemodynamics of the human extremities during postural exposures]. / Uprugie svoistva arterii i gemodinamika v konechnostiakh cheloveka pri postural'nykh vozdeistviiakh.

A non-invasive method was applied to estimation of elastic properties, the effective inner radius, blood pressure, and a number of other parameters in limb arteries of healthy men under postural effects. The changes in elastic properties of arteries were shown to occur only in the lower limbs where gradient of hydrostatic pressure changed during the examination. In the arms, where this gradient is practically absent, elastic properties of arteries remained the same. The data obtained indicate that gradient of hydrostatic pressure is responsible for the changes observed.

[Role of changes in blood volume and linear velocity in the formation of pulsatile electrical impedance oscillations]. / Rol' izmenenii ob"ema krovi i lineinoi skorosti ee dvizheniia v formirovanii pul'sovykh kolebanii élektricheskogo impedansa.

Measurements of the module of the blood electrical impedance by means of tetrapolar rheography method with the electrodes placed both outside and inside of the pig aortical preparation revealed the vessel blood volume oscillations dependence on the blood flow velocity, the latter increment relation to the pulsatile impedance changes. Under life conditions the pulsatile oscillations of the blood flow electrical impedance were fully dependent on the vessel volume changes.