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A Novel Deep-Intronic CFAP44 Variant Underlies Multiple Morphological Abnormalities of the Sperm Flagella
Yaxian Ma1,2, Yuecheng Yang3,4, Tong Zhang1,2
1Department of Reproductive Medicine and NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People's Hospital of Yunnan Province & The Affiliated Hospital of Kunming University of Science and Technology, Kunming, People's Republic of China.
Purpose:
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.
Patients And Methods:
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.
Results:
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.
Conclusion:
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.
Insights
A novel CFAP44 gene variant was identified in a Chinese family with multiple morphological abnormalities of the sperm flagella (MMAF). This deep-intronic variant disrupts sperm flagella formation, confirming its role in male infertility.
Area of Science:
- Genetics
- Reproductive Biology
- Molecular Biology
Background:
- Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare cause of primary male infertility.
- Sperm flagella are essential for sperm motility and fertilization.
- CFAP44 is crucial for flagella assembly and its variants are implicated in MMAF.
Purpose of the Study:
- To identify the genetic cause of MMAF in an infertile Chinese male patient.
- To investigate the pathogenicity of a novel CFAP44 variant.
- To expand the understanding of CFAP44's role in male infertility.
Main Methods:
- Whole-exome sequencing (WES) was performed on an infertile patient.
- Sanger sequencing confirmed the identified variant in the family.
- In silico analyses, minigene splicing assays, and RT-PCR were used to assess variant pathogenicity.
Main Results:
- A novel homozygous deep-intronic CFAP44 variant (c.1890+5G>C) was identified.
- The variant was confirmed to cause exon 15 skipping, leading to a deletion in the CFAP44 transcript.
- This disruption affects normal CFAP44 splicing and flagella formation.
Conclusions:
- This study reports the first homozygous CFAP44 variant causing MMAF in a Chinese family.
- The identified deep-intronic variant is pathogenic and contributes to male infertility.
- This finding enhances the understanding of CFAP44's role in MMAF and provides a basis for genetic counseling.
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