A Novel Deep-Intronic CFAP44 Variant Underlies Multiple Morphological Abnormalities of the Sperm Flagella.

Authors

Yaxian Ma, Yuecheng Yang, Tong Zhang, Daoheng Hu, Yuancun Zhao, Xuancheng Mai, Junxue Ni, Jie Zhang

Published in

The application of clinical genetics. Volume 19. Pages 609696. Epub Jun 24, 2026.

Abstract

Multiple morphological abnormalities of the sperm flagella (MMAF), uncommonly causing primary infertility, are typical features of aberrant spermatozoa flagellum morphologies, which manifest as shortness, absence, bending, coiling, and irregularity of flagella. CFAP44, an important component of flagella assembly, has attracted significant interest due to its critical role in MMAF pathogenesis. Understanding the variants associated with CFAP44 can provide insights into the molecular mechanisms underlying MMAF.
A comprehensive clinical evaluation was conducted on an infertile Chinese male patient from a nonconsanguineous family with sever asthenozoospermia (no progressive sperm). By performing whole-exome sequencing (WES), a novel variant of CFAP44 was identified. Sanger sequencing was performed to confirm the variant. To better investigate its pathogenicity, In silico variant analyses, minigene splicing assays and RT-PCR in vivo were performed.
As a result, a CFAP44 homozygous deep-intronic variant (NM_001164496.1:c.1890+5G>C) was detected in the proband by WES. Sanger sequencing confirmed this variant in this family. Splice site prediction suggested that this variant may be a disease-causing variant. Then, exon 15 skipping was identified through minigene assays and RT-PCR in vivo, resulting in a 111-bp deletion within the mutated sequence, thereby indicating a disruption in the normal splicing of the CFAP44 transcript.
This is the first study to detect a homozygous variant (c.1890+5G>C) within the CFAP44 gene causing MMAF in a Chinese family. Our results confirmed the pathogenicity of this deep-intronic variant and expanded the mutational spectrum of the CFAP44 gene. Consequently, this study may help elucidate the effect of CFAP44 on MMAF and provide a theoretical basis for MMAF.

PMID:
42371530
Bibliographic data and abstract were imported from PubMed on 29 Jun 2026.

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