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Spermatogenic failure, X-linked, 6(SPGFX6)

MedGen UID:: 1840198
•Concept ID:: C5829562
•: Disease or Syndrome

Synonym:	SPGFX6

Gene (location): Gene(s) directly associated with this condition or phenotype.	USP26 (Xq26.2)

Monarch Initiative:	MONDO:0859478
OMIM®:	301101

Definition

X-linked spermatogenic failure-6 (SPGFX6) is characterized by male infertility due to asthenoteratozoospermia. Patient spermatozoa show reduced progressive motility, and multiple morphologic abnormalities of the flagella (MMAF) are observed, primarily short and coiled flagella. Pregnancy can be achieved by intracytoplasmic sperm injection (ICSI) (Liu et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). [from OMIM]

Clinical features

From HPO

Male infertility

MedGen UID:: 5796
•Concept ID:: C0021364
•: Disease or Syndrome

The inability of the male to effect fertilization of an ovum after a specified period of unprotected intercourse. Male sterility is permanent infertility.

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Abnormal male external genitalia morphology

MedGen UID:: 871399
•Concept ID:: C4025897
•: Anatomical Abnormality

Any structural abnormality of male external genitalia.

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Reduced sperm motility

MedGen UID:: 907698
•Concept ID:: C4082176
•: Finding

An abnormal reduction in the mobility of ejaculated sperm.

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Short sperm flagella

MedGen UID:: 1623693
•Concept ID:: C4539787
•: Finding

Sperm cells with abnormally short flagella.

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Coiled sperm flagella

MedGen UID:: 1611216
•Concept ID:: C4539789
•: Finding

Sperm cells whose flagella are twisted (coiled).

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Microcephalic sperm head

MedGen UID:: 1640115
•Concept ID:: C4693760
•: Finding

Decreased size of the head of sperm.

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Reduced progressive sperm motility

MedGen UID:: 1730031
•Concept ID:: C5436680
•: Finding

A reduced proportion of sperm that move in a straight line or large circles; alternatively, an increased proportion of sperm that move in tight circles or in some other non-linear fashion.

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Absent sperm axoneme central pair complex

MedGen UID:: 1785608
•Concept ID:: C5539658
•: Finding

Absence of the central pair of microtubules in the sperm axoneme, thereby forming a 9+0 pattern instead of the normal 9+2 pattern.

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Recurrent pneumonia

MedGen UID:: 195802
•Concept ID:: C0694550
•: Disease or Syndrome

An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.

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Recurrent bronchitis

MedGen UID:: 148159
•Concept ID:: C0741796
•: Disease or Syndrome

An increased susceptibility to bronchitis as manifested by a history of recurrent bronchitis.

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Recurrent otitis media

MedGen UID:: 155436
•Concept ID:: C0747085
•: Disease or Syndrome

Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.

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Abnormality of the genitourinary system
Abnormality of the immune system
- Recurrent otitis media
Abnormality of the respiratory system
- Recurrent bronchitis
- Recurrent pneumonia

Recent clinical studies

Etiology

Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.

Hardy JJ, Wyrwoll MJ, Mcfadden W, Malcher A, Rotte N, Pollock NC, Munyoki S, Veroli MV, Houston BJ, Xavier MJ, Kasak L, Punab M, Laan M, Kliesch S, Schlegel P, Jaffe T, Hwang K, Vukina J, Brieño-Enríquez MA, Orwig K, Yanowitz J, Buszczak M, Veltman JA, Oud M, Nagirnaja L, Olszewska M, O'Bryan MK, Conrad DF, Kurpisz M, Tüttelmann F, Yatsenko AN; GEMINI Consortium
Hum Genet 2021 Aug;140(8):1169-1182. Epub 2021 May 7 doi: 10.1007/s00439-021-02287-y. PMID: 33963445 Free PMC Article

Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1.

Lopes AM, Aston KI, Thompson E, Carvalho F, Gonçalves J, Huang N, Matthiesen R, Noordam MJ, Quintela I, Ramu A, Seabra C, Wilfert AB, Dai J, Downie JM, Fernandes S, Guo X, Sha J, Amorim A, Barros A, Carracedo A, Hu Z, Hurles ME, Moskovtsev S, Ober C, Paduch DA, Schiffman JD, Schlegel PN, Sousa M, Carrell DT, Conrad DF
PLoS Genet 2013 Mar;9(3):e1003349. Epub 2013 Mar 21 doi: 10.1371/journal.pgen.1003349. PMID: 23555275 Free PMC Article

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Diagnosis

Genomic testing for copy number and single nucleotide variants in spermatogenic failure.

Hardy J, Pollock N, Gingrich T, Sweet P, Ramesh A, Kuong J, Basar A, Jiang H, Hwang K, Vukina J, Jaffe T, Olszewska M, Kurpisz M, Yatsenko AN
J Assist Reprod Genet 2022 Sep;39(9):2103-2114. Epub 2022 Jul 18 doi: 10.1007/s10815-022-02538-5. PMID: 35849255 Free PMC Article

Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.

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