In other species: domestic cat , puma , horse , pig , Arabian camel , llama , taurine cattle , goat , sheep , domestic yak , alpaca

Categories: Reproductive system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 219050 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0009047: cryptorchidism

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: no

Cross-species summary: Failure of one (unilateral) or both (bilateral) testes to descend.

Species-specific description: Cryptorchidism is characterized by the presence of one or two undescended testes in an otherwise phenotypically normal male (isolated cryptorchidism). Canine cryptorchidism is common in the dog population as a whole, with high prevalence in some breeds. Undescended testes have an increased risk of developing neoplasia. Breeding of affected dogs is discouraged. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT, modified by Imke Tammen [28/09/2023]

Inheritance: Inheritance of this condition is recessive and polygenic, with contributions from epigenetic and environmental factors (Zhao et al., 2010).

Mapping: By conducting a GWAS on 106 affected and 99 normal male Siberian Huskies, each genotyped with the 170K CanineHD BeadChip (yielding 120,379 informative SNPs), Zhao et al. (2014) identified "six putative genomic candidate regions on CFA6, 9, 24, 27 and X". Blades et al. (2022) identified a variant in HMGA2 that was associated with inguinal cryptorchidism in an across-breed GWAS, but within-breed GWAS failed to replicate this association in any breed, and failed to identify any other potential marker.

 

Markers: Krzeminska et al. (2020) concluded that a "SNP in CYP17A1 and an indel in CYP19A1 . . . cannot be considered markers associated with a predisposition to cryptorchidism".

Stachowiak et al. (2024) "The gonadal transcriptome of nine unilaterally cryptorchid dogs and seven control dogs was analyzed using RNA-seq. ... Validation studies in larger cohorts of cryptorchid (n = 122) and control (n = 173) dogs showed that the TT genotype (rs850666472, p.Ala1230Val) and the AA genotype in 3'UTR (16:23716202G>A) in KATA6, responsible for acetylation of lysine 9 in histone H3, are associated with cryptorchidism (P = 0.0383). Both the transcript level of KAT6A and H3K9 acetylation were lower in undescended testes, and additionally, the acetylation depended on the genotypes in exon 17 and the 3'UTR. Our study showed that the massive alteration of the transcriptome in undescended testicles is not caused by germinal DNA variants in DEG regulatory sequences but is partly associated with an aberrant DNA methylation and H3K9 acetylation patterns. Moreover, variants of KAT6A can be considered markers associated with the risk of this disorder."

Clinical features: Undescended testes may be located anywhere from the caudal pole of the kidney to the inguinal canal, or outside of the canal but cranial to the scrotum (Meyers-Wallen, 2011). Canine testes normally pass through the inguinal canal within 10 days after birth (Gier and Marion, 1969), but scrotal testes are not easily palpable in neonates. Dogs can be considered cryptorchid if one or both testes are not palpable in the scrotum by 6 to 8 weeks of age (Meyers-Wallen, 2011). Later testis descent can occur, and is more common with unilaterally cryptorchid dogs (Dunn et al., 1968).

Pathology: There is an increased risk of neoplasia (Sertoli cell tumor, seminoma) in undescended testes. Unilateral cryptorchid dogs may have reduced fertility and bilateral cryptorchid dogs are sterile, as spermatogonia are depleted in undescended testes. Cryptorchid testes can occur in association with other DSD, such as Persistent Mullerian duct syndrome, AMHR2-related in Miniature Schnauzers (OMIA:002775-9615) and XX difference of sexual development (OMIA:000901-9615) in several breeds. As testes descend, they transit through the abdomen and inguinal canal to the scrotum. Testosterone and INSL3 (insulin like factor 3), both secreted by Leydig cells, induce the growth and differentiation in the gubernaculum, which is needed for normal testicular descent. Mutations in INSL3 or its receptor (LGR8/GREAT) cause cryptorchidism in humans, but no analogous mutations have been discovered in dogs. Human males with heterozygous INSL3 mutations are unilaterally cryptorchid at birth, but the testis descends later, usually at puberty (Tomboc et al., 2000, Ferlin et al., 2003). Other candidate genes for cryptorchidism in humans are the androgen receptor (AR) and estrogen receptor (ER, Pathirana, 2010).

Prevalence: Canine isolated cryptorchidism is common, with different studies reporting prevalence from 6.8% of males presented for neutering to 1.4% of dogs at 6-12 months of age (Hayes et al., 1985, Yates et al., 2003). Prevalence is higher in Siberian Husky dogs, and in smaller breeds compared to larger breeds (Zhao et al., 2010, Pathirana et al., 2010).

Control: Breeding of fertile cryptorchid animals (as well as their parents or siblings) is discouraged. The AVMA states that it is unethical for a veterinarian to surgically correct cryptorchidism without also sterilizing the animal.

Genetic testing: There are no reliable genetic tests available at this time.

Breed: Siberian Husky (Dog) (VBO_0201233).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).