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Table 1 Comparison of the clinical phenotypes of 46,XX SRY-negative male patients with CNV of SOX3

From: Identification of an SRY-negative 46,XX infertility male with a heterozygous deletion downstream of SOX3 gene

Case

References

CNV

Clinical phenotype

Detection method

X chromosome inactivation

1

Sutton E et al. 2011[12]

The patient contained two microduplications of approximately 123 kb and 85 kb, the former of which spanned the entire SOX3 gene

The patient was an infertility male of 30-year-old. His height was 165 cm, and he weighed 64 kg, with no abnormal symptoms. Infertility was indicated by two spermograms, which confirmed azoospermia. The patient presented with small testicles and typical secondary sexual characteristics

CMA

X-inactivation studies showed no evidence for skewed inactivation in DNA derived from lymphocytes

2

Sutton E et al. 2011[12]

The patient contained a single 343-kb microdeletion immediately upstream of SOX3; the coding sequence of SOX3 is not affected

It is suggested that altered regulation (and not increased dosage) of SOX3 is the cause of XX male sex reversal

The patient was a 35-year-old with gender dysphoria. Height was 167.5 cm, weight 73.5 kg, with no medical problems apart from ongoing gender identity issues. The external genitalia was typical male, apart from small, soft 6-ml testes. There was little body hair. Primary hypogonadism, with FSH and LH elevated, and testosterone low. Histological examination showed that atrophic changes in the testes, without normal spermatogenesis, thickening and hyalinization of the tubular basal lamina, and diminished interstitial cells. The patient was SRY-negative in both peripheral blood and testicular tissue. The SOX3 rearrangement was not present in his mother

CMA

NA

3

Sutton E et al. 2011[12]

The patient has a large duplication fragment (approximately 6-Mb) encompassing SOX3 and at least 18 additional distally located genes. The overexpression of SOX3 probably contributes to the phenotypic complexity. Notably, the proximal breakpoint falls within the SOX3 regulatory region

The patient was a boy of 19 months who presented some complex phenotypes, including scrotal hypoplasia, microcephaly, unilateral small testis, developmental delay, growth retardation. There were no significant problems during pregnancy or the newborn period. No endocrine evaluation or parental DNA was available

CMA

NA

4

Moalem S et al. 2012[24]

The patient has a de novo copy number gain of 494-kb in the region of Xq27.1 (NCBI 36/hg18: 139,354,859–139,848,664), containing the SOX3, RP1-177G6.2, CDR1 and MIR320D2 genes

The patient was a 46,XX male newborn with hypospadias. Ultrasound examination revealed normal testicular size and structure

CMA

NA

5

Grinspon RP et al. 2016[25]

The patient has a de novo gain at Xq27.1. The duplicated region was around 0.5 Mb, and encompassed the SOX3 gene (arr[hg19] Xq27.1(139,541,737–140,043,863) × 3). Other genes included were RPS17P17, CDR1, MIR320D2

The patient was a two years six months boy. He had a trophic phallus 32 mm long and 13 mm wide with ambiguous genitalia and bilateral ovotesticular DSD

CMA

NA

6

Tasic V et al. 2019[27]

The patient has a 550-kb duplication at Xq27 (ChrX: 139,360,520–139,908,320), involving SOX3, the non -coding RNA LINC00632, AK054921, CDR1 and the miRNA MIR320D2

The patient was an 11-year-old boy with right kidney hypoplasia and moderate coronal hypospadias. His testes volume was > 4 mL, and the penis length was 5 cm

CMA

NA

7

Present study

The patient had a heterozygous deletion of about 867 kb in Xq27.1 (138,612,879–139,480,163 bp), located at 104 kb downstream of SOX3 gene, including F9, CXorf66, MCF2 and ATP11C in CMA analysis. WGA also displayed the above deletion fragment but did not present known pathogenic or likely pathogenic SNV&InDel mutation responsible for sex determination and development

The patient was a 31-years-old primary infertility patient with two small testicular, his height was 166 cm, and he weighed 52.5 kg. Physical examination showed a male appearance, a trim beard, Adam's apple, the testicles are the size of broad bean, the penis is average size. No sperm was found in routine semen examination. Hormone test results showed that testosterone and estradiol were low and that FSH and LH were high. The parental sample was unavailable

CMA, WGA

The X chromosome inactivation ratio of the patient was about 75%, which was non-random inactivation