Balkan Journal of Medical Genetics

DUPLICATION OF THE SOX3 GENE IN AN SRY-NEGATIVE 46,XX MALE WITH ASSOCIATED CONGENITAL ANOMALIES OF KIDNEYS AND THE URINARY TRACT: CASE REPORT AND REVIEW OF THE LITERATURE
Tasic V1, Mitrotti A2, Riepe FG3, Kulle AE3, Laban N1, Polenakovic M4, Plaseska-Karanfilska D4, Sanna-Cherchi S2, Kostovski M1, Gucev Z1,*
*Corresponding Author: Professor Dr. Zoran Gucev, University Children’s Hospital, Medical Faculty Skopje, ul. Majka Tereza 17, 1000 Skopje, Republic of Macedonia. Mobile: +389-70-279-742. E-mail: gucevz@ gmail.com
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INTRODUCTION

Sex in humans is genetically determined and is defined by the sex chromosomes (XY for males and XX for females) and by the development of gender specific anatomy, physiology and behavior. A complete or partial mismatch between genetic sex and phenotypic sex results in disorders of sexual development (DSD). Disorders of sexual development in humans have a frequency of at least one in 100 live births [1], while the frequency of “corrective” genital surgery is estimated to be between one and two per 1000 live births. There is a wide spectrum of DSD ranging from hypospadias (incidences variable from one in 500 to six in 250 births) [2] to ambiguous genitalia (incidence one in 4500 births) [3] and complete sex reversal (46,XY females and 46,XX males; one in 20,000 births) [4]. Congenital malformations of the kidney and DSD are often described in association, in the broad spectrum of multiple malformation syndromes, as it happens in Smith-Lemli-Opitz Syndrome (OMIM: 270400), a complex syndrome characterized by congenital kidney and ureteric abnormalities associated with genital anomalies and inadequate sexual hormone production [5,6]. Mutations of Wilms tumor 1 (WT1) gene may lead to Denys-Drash syndrome (OMIM: 19408), Frasier syndrome (OMIM: 13668) or Wilms aniridia genitourinar renal (WAGR) syndrome (OMIM: 194072), which are characterized by kidney and genitourinary diseases in association with internal and external genitalia defects [7-10] and mostly 46,XY female phenotypes. The sex-determining region Y (SRY) is considered to be the main regulator of male sex determination in mammals [1,11]. The main function of SRY in sex determination is to upregulate its direct target gene SOX9, thus initiating Sertoli cell differentiation [12,13,14]. The SRY-related HMG box-containing gene 3 (SOX3) is a member of a family of 20 SOX genes, structurally similar to SRY [15]. This gene is located on the X chromosome and it consists of a single exon [16]. The SOX3 gene encodes for a transcription factor expressed in the central nervous system (CNS) of vertebrate embryos, which is essential for pituitary, craniofacial and neuronal development [15-22]. Prior human genetics studies implicated SOX3 in brain development and gender determination. Laumonnier et al. [17] described a pericentric inversion of the X chromosome involving the IL1RAPL at Xp21.3 and the polyalanine repeat of SOX3 at Xq26.3, in a 10-year-old girl affected a by mild memory deficiency, strabism, speech impairment and hypotonia; because previous studies showed that female carriers of microdeletions involving IL1RAPL do not show intellectual disability [23,24], the phenotype was likely attributable to another gene in the duplicated region. Analysis of an independent family segregating X-linked intellectual disability demonstrated an in-frame duplication of 33 bp involving a polyalanine repeat of SOX3, thus pointing to SOX3 mutations as the cause of neurodevelopmental delay. A sub-microscopic duplication of 685.6 kb at Xq27.1 involving SOX3, has been reported in two siblings affected by hypopituitarism and abnormalities of corpus callosum, while a duplication involving the SOX3 polyalanine repeat was identified in three male siblings from another family, segregating panhypopituarism and abnormalities of the pituitary gland: all of these patients had absent infundibulum and did not present an intellectual disability [18]. A duplication of 3.9 Mb involving the Xq27 region containing SOX3, has been reported in males affected by X-linked hypopituitarism [25]. In a study of 16 SRY-negative 46,XX male patients, DNA microarray analysis showed genomic rearrangements of the SOX3 regulatory region in three patients, two duplications and one deletion: the CNVs involved genomic regions in close proximity of SOX3 in all three patients [26]. Interestingly, a recent report described a SRY-negative, 46,XX boy affected by ovotesticular DSD, with hypo-spadias and cryptorchidism with a de novo duplication of a 502 kb fragment of the long arm of chromosome X, involving SOX3, as well as RPS17P17, CDR and MIR 320D2. The role of the RPS17P17, CDR1 and MIR320D2 genes has not been investigated [27]. In summary, SOX3 genetic variants have been associated with X-linked intellectual disability with isolated growth hormone deficiency as well as X-linked panhypopituitarism and 46,XX sex reversal in males. Until now, no other developmental phenotypes have been associated to SOX3 gene dosage.

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