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MPS on 3.6 mL plasma from pregnant mothers could potentially provide the diagnosis of CAH, noninvasively, before the ninth week of gestation. Only affected female fetuses will thus be treated. Our strategy represents a generic approach for noninvasive prenatal testing for an array of autosomal recessive disorders.

Steroid 17β-hydroxysteroid dehydrogenase III (17β-HSD3) deficiency is a rare autosomal recessive disorder that usually presents in patients with a 46,XY karyotype with ambiguous genitalia at birth. The 17β-HSD3 enzyme, which is encoded by the HSD17B3 gene, converts gonadal delta-4 androstenedione (Δ4) to testosterone (T). Such 17β-HSD3 enzyme deficiency is expected to lead to an increased ratio of D4 to T when the patient undergoes a human chorionic gonadotropin stimulation (hCG) test. Two patients with 46,XY disorders of sexual differentiation were studied. Serum D4 and T levels were measured by HPLC tandem mass spectrometry. As one of the patients was born to consanguineous parents, we performed single nucleotide polymorphism (SNP) microarray to analyze regions of homozygosity (ROH). The HSD17B3 gene was sequenced using the Sanger method. Contrary to expectations, both patients demonstrated decreased D4/T ratio after hCG stimulation. Initial sequencing results for the androgen receptor or 5α-reductase were negative for mutations. ROH analysis identified HSD17B3 as a candidate gene that might cause the disease. Sanger sequencing of the HSD17B3 gene confirmed 17β-HSD3 deficiency in both patients. Serum D4/T ratios are not reliable parameters for the diagnosis of 17β-HSD3 deficiency. Molecular genetic analysis provides accurate diagnosis.

24 25 45 KEYWORDS 46 Atherosclerotic plaque, T cells, macrophages, cerebrovascular events, Stroke, CyTOF, 47 scRNA-seq, CITE-seq, cell-cell interactions, IL-1β, PD-1, T cell exhaustion. 48 49 alterations of individual immune cells that contribute to human disease and its CV 89 complications. 90 91 RESULTS 92 Single-Cell Immunophenotyping of Human Atherosclerosis: Study Design 93 To map the immune microenvironment of atherosclerotic lesions, identify mirroring 94 immune changes in blood and pinpoint cell-specific alterations associated with clinical CV 95 events (i.e. stoke and TIA), we performed a large-scale CyTOF mass-cytometry 96 analysis 41 combined with Cellular Indexing of Transcriptomes and Epitopes by 97 Sequencing (CITE-seq) 42 and single-cell scRNA-seq analysis of plaques from a total of 98 46 prospectively enrolled patients undergoing carotid endarterectomy (Fig.

Congenital adrenal hyperplasia (CAH) describes a family of inherited disorders whose common feature is impaired cortisol synthesis. Cortisol is produced from cholesterol in the adrenal glands through a series of enzymatic reactions. A genetic mutation of the gene encoding one of these enzymes can lead to CAH. In some forms of CAH, a build up of steroid precursors to the defective enzyme leads to an overproduction of androgens, sex steroids, causing to virilization of a female foetus affected with CAH. Most cases of CAH are owed to a defect in the enzyme, 21‐hydroxylase. This family of disorders is treatable with oral glucocorticoids. Key Concepts: Congenital adrenal hyperplasia describes a group of autosomal recessive genetic defects in the enzymes of steroidogenesis. The adrenal glands produce steroids including glucocorticoids, mineralocorticoids and sex steroids (androgens). Deficiency of 21‐hydroxylase causes more than 90% of cases of CAH and is characterised by glucocorticoid and mineralocorticoid deficiency associated with virilization in females. There are two forms of CAH: the classical form, which includes the salt‐wasting and the simple virilizing forms and the nonclassical form, which is associated with milder symptoms. The main goals of medical therapy for CAH are to replace deficient cortisol with a suitable glucocorticoid, deficient aldosterone with mineralocorticoid replacement and sodium supplements, and to prevent excessive androgen secretion. Prenatal dexamethasone treatment can prevent genital ambiguity in an affected female foetus with classical CAH. The presence of cell‐free foetal DNA in maternal plasma has opened up new possibilities for noninvasive prenatal testing of 21‐hydroxylase deficiency and other genetic steroid disorders.