CMA = chromosomal microarray; DSD = disorders/differences of sex development; FISH = fluorescent in situ hybridization; GS = genome sequencing; NA = not applicable

Genes are listed in alphabetic order.

See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in these genes.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. Sequencing will typically detect presence of a gene but not chromosomal location.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the regions surrounding SOX3 and SOX9. CMA will typically detect presence or absence of a chromosomal region but not the location of that region in relationship to other chromosomal regions.

Genome sequencing is typically performed by next-generation sequencing of sheared genomic DNA. Genome sequencing techniques have nonstandardized, highly variable coverage. Unlike exome sequencing, genome sequencing has the ability to identify structural variants and chromosome breakpoints in noncoding regions. The coverage of the genome is less than 100% and varies by laboratory.

Bashamboo et al [2016], Baetens et al [2017], Igarashi et al [2017], Knarston et al [2019]

To date, the only pathogenic variants in NR5A1 identified as causing nonsyndromic 46,XX testicular DSD affect the Arg92 codon.

Due to the mechanism of disease causation, copy number variants in this gene are unlikely to lead to nonsyndromic 46,XX testicular DSD.

Croft et al [2018b]

Sutton et al [2011], Moalem et al [2012], Vetro et al [2015]

Depending on the microarray platform used and the probe coverage in and around SOX3 and SOX9, these variants may not be detected by CMA.

It is important to verify with the testing laboratory that they will report variants in the gene desert around SOX9, as these may be overlooked and thus not reported.

Fechner et al [1993], McElreavey et al [1993], Boucekkine et al [1994]

As implied by the title of this table, sequence analysis that detects the present of SRY only leads to nonsyndromic 46,XX DSD in individuals with a known 46,XX chromosome complement and not to those with a 46,XY chromosome complement.

Gomes et al [2019], Eozenou et al [2020]

The only pathogenic variants described in individuals with this phenotype specifically affect the ZF4 domain (see Genetically Related Disorders and Molecular Genetics).