Homozygosity on Chromosome 6 Without Paternal Transmission
A 3-year-old boy has a recessive disorder mapped to chromosome 6. Exome sequencing shows a homozygous frameshift variant in a gene at 6p. The mother is heterozygous for the variant. The father’s blood DNA shows no variant at >100× coverage, and his semen DNA is also negative. The boy’s karyotype is 46,XY. Chromosomal microarray shows no deletion or duplication, but SNP analysis shows only maternal alleles across the entire chromosome 6, with no paternal contribution. The parents are non-consanguineous and healthy. The variant has a population allele frequency of about 1 in 500,000. The boy has no dysmorphic features. The mother is now 10 weeks pregnant and asks about recurrence. The clinician must decide whether this is maternal uniparental isodisomy, a paternal deletion, or a sample-handling error, and what prenatal testing to offer.
1. Explain how the boy can be homozygous for a maternal variant when the father is not a carrier.
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The SNP data show no paternal alleles across chromosome 6, so the boy has two maternal copies of this chromosome. This is maternal uniparental disomy. Because the two maternal copies are identical along the chromosome, the boy is homozygous for the maternal frameshift variant. A paternal deletion is excluded by the normal chromosomal microarray and by the absence of a deletion at 6p; a sample swap is unlikely because the maternal heterozygosity and the child’s homozygous variant are consistent with the SNP pattern. The mechanism is maternal uniparental isodisomy: a single maternal chromosome 6 was duplicated, or an early mitotic recombination produced two copies of the same maternal homolog. The father’s lack of the variant is therefore not contradictory; his chromosome 6 was not transmitted.
2. What recurrence risk should be quoted for the next pregnancy, and what prenatal testing is appropriate?
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The recurrence risk for uniparental disomy itself is low, generally well under 1%, because it usually arises from a sporadic meiotic or mitotic error. The mother is a carrier, so each pregnancy has a 50% chance of inheriting her variant and being a carrier, but an affected child requires two maternal copies of chromosome 6 or a second paternal event. The couple should not be quoted a 25% autosomal recessive risk, because the father is not a carrier. Prenatal testing should test both the variant and chromosome 6 inheritance: chorionic villus sampling or amniocentesis with SNP microarray or a chromosome 6 marker panel, plus targeted variant testing. Testing the variant alone could miss a recurrent uniparental disomy or misclassify a carrier as unaffected. Genetic counseling should also address the low but nonzero possibility of a recurrent UPD and the uncertainty inherent in a single family.
3. Suppose the father’s semen DNA instead showed 5% of reads carrying the same variant. How would that change the interpretation and counseling?
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A 5% variant fraction in semen would indicate paternal germline mosaicism, not uniparental disomy. The child’s SNP array would then be expected to show paternal alleles across chromosome 6, rather than only maternal alleles. If the father is mosaic, some sperm carry the variant, so the risk per pregnancy is approximately the mosaic fraction in sperm multiplied by the mother’s 50% transmission probability. With 5% mosaic sperm, the risk of an affected child from co-inheritance of the paternal and maternal variants would be about 2.5%, plus the low background UPD risk. This is very different from the near-zero UPD recurrence risk. Counseling would need to explain that the risk is uncertain because the mosaic fraction in testis may differ from semen, and prenatal testing should again combine variant testing with SNP analysis to determine parental origin.