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Table 1 Genotype-phenotype relationship, genetic testing and preimplantation genetic diagnosis (PGD) in hemophilia A

From: Preimplantation genetic diagnosis of hemophilia A

Mutation type Frequency of occurrancea Clinical severityb Test method PGD method
Inversion
• INV22
• INV1
47 %
• 45 %
• 2 %
Severe • I-PCR (for INV22)
• Long-distance PCR (for INV22)
• Southern blotting (for INV22)
• Multiplex PCR (for INV1)
• Linkage analysis
Point mutation
• Missense
• Nonsense
• Splicing site
28 %
• 15 %
• 10 %
• 3 %
Mild, Moderate, Severe
• Mild, Moderate (majority)
• Severe (majority)
• Severe (majority)
Direct DNA sequencing • ARMS-qPCR
• Linkage analysis
Small deletion/insertion (<1 exon) 16 % Severe (majority) Direct DNA sequencing • ARMS-qPCR
• Linkage analysis
Large deletion (≥1 exon) 3 % Severe (majority) MLPA • Linkage analysis
Others (e.g., Complex rearrangement) NA Severe (majority) Depending on mutation entities • Linkage analysis
  1. MLPA multiplex ligation-dependent probe amplification, I-PCR inverse polymerase chain reaction, ARMS amplification refractory mutation system, NA not available
  2. aSee the review in Gouw et al., [12]
  3. bHA patients are clinically divided into three different severities based on the residual FVIII coagulant activity (FVIII:C): severe (FVIII:C < 1 % of normal level), moderate (FVIII:C is 1–5 % of normal level) and mild (FVIII:C is 5–30 % of normal level)