RESUMO
Infertility affects about 15% of heterosexual couples and male factors account for ~45-50% of clinical cases. Genetic factors play an important role in male infertility and thus we try to develop a cost-effective method for screening the genetic factors in male infertility. In our retrospective proof-of-concept study, we employed the high-throughput ligation-dependent probe amplification (HLPA) to examine the copy number by 115 genomic loci covering the Y chromosome, and 5 loci covering the X chromosome-specific region. We identified 8 sex chromosome aneuploid people from the low sperm concentration (LSC) group, and Y chromosome-specific microdeletion/duplications in 211 samples from the LSC group, and in 212 samples from the control group. 35 samples showed complete loss of AZFc (BPY2 to CDY1B deletion), which was not observed in controls. Nevertheless, a partial loss of AZFc (BPY2 to BPY2B deletion) was detected at comparable frequencies in both groups (68/211 vs. 108/212, respectively). And we further found structural variations in 28.6 and 26.9% samples from infertility and fertility groups. Moreover, we found that there were lower copy numbers for heterochromatic sequences in men with LSC. Especially, we reported that ultra-low relative copy number (RCN) (<0.5) type and low RCN (0.5 to <0.75) type in Yq12 were more often in the LSC group for the first time. Our results not only shed light on the potential role of low RCN in Yq12 in male infertility but also showed that HLPA can be a powerful and cost-effective tool for clinical screening in male infertility.
Assuntos
Cromossomos Humanos Y/genética , Variações do Número de Cópias de DNA/genética , Loci Gênicos/genética , Infertilidade Masculina/genética , Aberrações dos Cromossomos Sexuais , Proteínas de Ciclo Celular/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Infertilidade Masculina/diagnóstico , Cariotipagem/métodos , Masculino , Reação em Cadeia da Polimerase Multiplex , Proteínas Nucleares/genética , Oligospermia/diagnóstico , Oligospermia/genética , Proteínas de Ligação a RNA/genética , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Contagem de EspermatozoidesRESUMO
BACKGROUND: Biotinidase deficiency (OMIM 253260) is an autosomal recessively inherited disorder affecting about 1/60,000 people worldwide. The absence or deficiency of biotinidase impairs free biotin recycling and affects biotin-dependent carboxylase functions. METHODS: A Chinese patient with spontaneous recurrent epilepsy, an eczema-like rash, hair loss, hypotonia, and hearing loss began at three months of age. Her biotinidase activity was 1.0 nmol/ml/min, 9.5% of the mean control activity, which confirmed profound biotinidase deficiency. RESULTS: Compound heterozygous for c.250-1G > C and c.878dupT variants in the BTD gene were identified in this patient. These two variants were novel and absent in the population matched controls and any databases. CONCLUSIONS: This study expanded the mutation spectrum of alterations of the BTD gene. Our patient also emphasized the critical role of biotinidase activity measurement combined with mutation analysis in early diagnosis of biotinidase deficiency.
Assuntos
Deficiência de Biotinidase/genética , Biotinidase/genética , Fenótipo , Adolescente , Biotinidase/metabolismo , Deficiência de Biotinidase/patologia , Feminino , Humanos , MutaçãoRESUMO
BACKGROUND: Genetic variants in TMPRSS3 have been causally linked to autosomal recessive nonsyndromic hearing loss (HL) at the DFNB8 and DFNB10 loci. These variants include both single nucleotide and copy number variations (CNVs). In this study, we aim to identify the genetic cause in three Chinese subjects with prelingual profound sensorineural HL. METHODS: We applied targeted genomic enrichment and massively parallel sequencing to screen 110 genes associated with nonsyndromic HL in the three affected subjects. CNVplex® analysis and polymerase chain reaction (PCR) were performed for CNV detection. RESULTS: We identified biallelic variations in TMPRSS3 including a novel complex genomic rearrangement and a novel missense mutation, c.551T>C. We have mapped the breakpoints of the genomic rearrangement and showed that it consisted of two deletions and an inversion encompassing exon 3 to exon 9 of TMPRSS3. CONCLUSION: Our study expanded the mutational spectrum of TMPRSS3 to include complex genomic rearrangements. It showcased the importance of an integrative approach to investigate CNVs and their contribution to HL.