Translating genomics to the clinical diagnosis of disorders/differences of sex development

Abstract

The medical and psychosocial challenges faced by patients living with Disorders/Differences of Sex Development (DSD) and their families can be alleviated by a rapid and accurate diagnostic process. Clinical diagnosis of DSD is limited by a lack of standardization of anatomical and endocrine phenotyping and genetic testing, as well as poor genotype/phenotype correlation. Historically, DSD genes have been identified through positional cloning of disease-associated variants segregating in families and validation of candidates in animal and in vitro modeling of variant pathogenicity. Owing to the complexity of conditions grouped under DSD, genome-wide scanning methods are better suited for identifying disease causing gene variant(s) and providing a clinical diagnosis. Here, we review a number of established genomic tools (karyotyping, chromosomal microarrays and exome sequencing) used in clinic for DSD diagnosis, as well as emerging genomic technologies such as whole-genome (short-read) sequencing, long-read sequencing, and optical mapping used for novel DSD gene discovery. These, together with gene expression and epigenetic studies can potentiate the clinical diagnosis of DSD diagnostic rates and enhance the outcomes for patients and families.

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations

“…Syndromic and non-syndromic causes have also been reported, but the etiology in many affected individuals remains broad due to the phenotypic overlap between individuals with partial androgen insensitivity and those with partial gonadal dysgenesis. [36][37][38] Individuals 5-12 had a wide spectrum of genitourinary phenotypes from partial gonadal dysgenesis with micropenis, hypospadias, and ambiguous genitals with Müllerian duct remnants to complete gonadal dysgenesis in a genotypic 46,XY individual with female external genitalia. Ppp1r12a has been noted to be increased in mouse striated and smooth muscle during sexual differentiation with higher levels in males than females.…”

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

“…Instead of comparing it with a control sample, as in the CGH, the SNP arrays compare the test sample with a pool of control samples available online. This technology can identify genetic gain or loss and, unlike the CGH array, is able to detect homozygosity, heterozygosity and consanguinity [ 11 , 89 ]. Parental samples are important to include in these approaches, to rule out inherited non-pathogenic polymorphisms.…”

“…With the reduction in the costs of next-generation sequencing and fast turnaround times, whole exome and genome sequencing have revolutionized the clinical testing for complex disorders, including DSD [ 10 , 11 , 12 ]. Whole exome sequencing allows the sequencing of approximately 95% of all the genomic protein coding regions.…”

“…DSD diagnosis has been advanced with the implementation of next-generation sequencing (NGS) methods such as whole exome and whole genome sequencing. This allows the detection of novel genes and regulatory regions affected in DSD [ 11 , 12 ]. While several Copy Number Variants (CNV) or single nucleotide polymorphisms (SNP) are detected per patient by NGS, it is difficult to determine the clinical relevance of such variance, requiring a better understanding of the exact genotype/phenotype correlation in DSD [ 10 ].…”

Transcriptional progression during meiotic prophase I reveals sex-specific features and X chromosome dynamics in human fetal female germline

“…Differences in X chromosome dosage between sexes are important for sexual dimorphism and fertility [ 17 ]. In female (XX) somatic cells, one of the two X chromosomes is silenced (XaXi) to equalize the expression of X-linked genes with male (XY) cells, a process known as X chromosome inactivation (XCI); moreover, in both female and male somatic cells, the active X chromosome is overexpressed to balance X-linked expression with that of the autosome pairs, a process known as X chromosome upregulation (XCU) (reviewed in [ 18 ]).…”