Disorders of sex development (DSD) are a group of rare conditions characterized by discrepancy between chromosomal sex, gonads and external genitalia. Congenital abnormalities of the kidney and urinary tract are often associated with DSD, mostly in multiple malformation syndromes. We describe the case of an 11-year-old Caucasian boy, with right kidney hypoplasia and hypospadias. Genome-wide copy number variation (CNV) analysis revealed a unique duplication of about 550 kb on chromosome Xq27, and a 46,XX karyotype, consistent with a sex reversal phenotype. This region includes multiple genes, and, among these, SOX3 emerged as the main phenotypic driver. This is the fifth case reporting a genomic imbalance involving the SOX3 gene in a 46,XX SRY-negative male, and the first with associated renal malformations. Our data provide plausible links between SOX3 gene dosage and kidney malformations. It is noteworthy that the current and reported SOX3 gene duplications are below the detection threshold of standard karyotypes and were found only by analyzing CNVs using DNA microarrays. Therefore, all 46,XX SRY-negative males should be screened for SOX3 gene duplications with DNA microarrays.

Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Analysis of Y chromosome haplogroups, defined by single nucleotide polymorphisms (SNPs), is now a standard approach for study of the origin of human populations and measurement of the variability among them. It is also a new forensic tool, because it may allow determination of the origin of any male sample of interest. We have used a strategy for rapid, simple and inexpensive Y chromosome SNP typing of 343 male DNA samples, of which 211 were Macedonians, 111 Albanians and 21 Roma, Serbs or Turks. Using multiplex polymerase chain reaction (mPCR) and a SNaPshot multiplex kit for single nucleotide extension reaction, 28 markers were grouped into five multiplexes. Twenty different Y haplogroups were found in these samples. The most common Y haplogroups in Macedonians were I2a-P37b (27.5%), E1b1b1a-M78 (15.6%), R1a1-SRY1532 (14.2%) and R1b1-P25 (11.4%). In the Albanians E1b1b1a-M78 accounted for 28.8%, R1b1-P25 for 18.0%, J2b2-M241 for 13.5% and R1a1-SRY1532 for 12.6%. We conclude that five haplogroups (E1b1b1a-M78, I2a-P37b, J2b2-M241, R1a1-SRY1532 and R1b1-P25) comprised 72.6% of the Y chromosomes, this being characteristic of the typical European Y chromosome gene pool.

Androgens are essential for male sexual develop ment and for fertility. They exert their action through the andro gen receptor (AR), a ligandactivated transcription factor. The 5' end of exon 1 of the AR gene includes a polymor phic CAG triplet repeat that varies in number between 10 to 36 in the normal population. There is controversy over an association between high CAG repeat numbers in the AR gene and male infertility. We have evaluated the pos sible effect of long CAG repeats in the AR on infertility in men from the Republic of Macedonia (R. Macedonia). A group of 222 infertile/subfertile males with different sperm counts and a control group of 152 proven fathers were studied. The CAG repeat number was determined by fluo rescent polymerase chain reaction (PCR) amplification of exon 1 of the AR gene analyzed by capillary electro phoresis. Mean CAG length did not differ significantly between males with azoospermia (22.0 ± 3.1), mild oligo zoospermia (22.4 ± 2.6), severe oligozoospermia (23.0 ± 4.2), normozoospermia (21.8 ± 2.4), or known causes of infertility (22.1 ± 2.9) and fertile controls (22.3 ± 2.9). However, we found a significantly higher percentage of CAG repeats >26 (p = 0.022), >27 CAG REPEAT NUMBER IN ANDROGEN RECEPTOR GENE AND MALE INFERTILITY

Steroid 5-α-reductase-2 (5-ARD) deficiency is a result of mutations of the SRD5A2 gene. It causes the disorder of sexual differentiation (DSD) in 46,XY individuals with a variable genital phenotype. We present two siblings with female external genitalia at birth and bilateral inguinal testes, raised as females. These are the first molecularly characterized patients from the Republic of North Macedonia (RN Macedonia) with a different clinical course due to the time of the diagnosis. Diagnosis of Patient 1 was based upon the detection of bilateral inguinal testes and testosterone/dihidrotestosterone ratio. Sex reversal was initiated by testes removal at the age of 20 months. Breast implantation and vaginoplasty were performed in adolescence and the girl is comfortable with the female sex. Her sibling, Patient 2, raised as a girl, was clinically assessed at 11.5 years due to the growth of phalus, deep voice and Adam’s apple enlargement. No change of gender was accepted. Complex molecular analysis including multiplex quantitative fluorescent polymerase chain reaction (PCR) screening for sex chromosome aneuploidies and SRY presence, Sanger sequencing combined with multiplex ligation-dependent probe amplification (MLPA), microarray-based comparative genomic hybridization (aCGH), and real-time PCR analysis for detection of exon copy number changes confirmed a novel c.146C>A (p.Ala49Asp) point mutation in the first exon inherited from the mother, and complete deletion of the first exon and adjacent regions inherited from the father. Novel genotype causing 5-ARD is presented. Genetic analysis is useful for the diagnosis and timely gender assignment in patients with 5-ARD. However, final gender assignment is difficult and requires combined medical interventions.