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Zorluk: OrtaGenetic and Molecular Mechanisms

A 27-year-old woman and her 29-year-old male partner present for preconception counseling. Both individuals have profound, nonsyndromic, bilateral congenital sensorineural hearing loss. They are otherwise healthy and take no medications. They are not consanguineous. Family histories reveal that the woman's parents both have normal hearing, but she has a brother with congenital hearing loss. The man's parents also have normal hearing, but he has a sister with congenital hearing loss.

Comprehensive genetic testing using a targeted next-generation sequencing panel is performed for both individuals. The results show that the woman is homozygous for a pathogenic nonsense mutation in the *GJB2* gene (which encodes connexin 26). The man is homozygous for a pathogenic missense mutation in the *SLC26A4* gene (which encodes pendrin). Neither individual carries a pathogenic variant in the other's affected gene.

Based on these genetic findings, which of the following is the most accurate statement regarding the expected outcome for their future offspring?

  1. The offspring will have normal hearing due to locus heterogeneity.Cevap
  2. B
    The offspring will have normal hearing due to allelic heterogeneity.
  3. C
    The offspring will have profound hearing loss, and invasive fetal genetic testing should be offered to confirm the variants.
  4. D
    The offspring will have profound hearing loss because both parents are homozygous for an autosomal recessive trait.
  5. E
    The offspring will have normal hearing but will require avoidance of cytochrome P450 inhibitors to prevent drug-induced ototoxicity.

Cevap

The offspring will have normal hearing due to locus heterogeneity.
The parents in this scenario both have congenital sensorineural hearing loss, but their conditions are caused by mutations in two entirely different genes (*GJB2* and *SLC26A4*). Because both forms of deafness are inherited in an autosomal recessive manner, an individual must have two mutated copies of the *same* gene to express the phenotype. The future offspring will inherit one mutated copy of *GJB2* from the mother and one mutated copy of *SLC26A4* from the father. Crucially, the offspring will also inherit a normal, functional copy of *GJB2* from the father and a normal, functional copy of *SLC26A4* from the mother. Therefore, the offspring will be a double heterozygote (a carrier for both conditions). Since the child will have at least one functional copy of each gene, they will have normal hearing. This phenomenon, where mutations at different genetic loci produce the same clinical disease phenotype, is called locus heterogeneity.

Adım Adım Çözüm

1
Analyze the maternal and paternal genotypes.
The mother has autosomal recessive hearing loss due to a homozygous mutation in GJB2. The father has autosomal recessive hearing loss due to a homozygous mutation in SLC26A4.
Establishing the specific affected loci for each parent is required to predict the offspring's genotype.
2
Determine the genotype of the future offspring.
The offspring will inherit one mutated GJB2 allele and one normal SLC26A4 allele from the mother, and one normal GJB2 allele and one mutated SLC26A4 allele from the father. The offspring will be a double heterozygote (a carrier for both conditions).
Mendelian independent assortment means the child receives one allele for every gene from each parent.
3
Correlate the genotype to the phenotype and identify the genetic principle.
Because both types of hearing loss are recessive, having one functional copy of both GJB2 and SLC26A4 ensures normal hearing. This phenomenon is known as locus heterogeneity.
Locus heterogeneity occurs when mutations at entirely different genetic loci produce the exact same clinical phenotype.

Anahtar Kavram

Locus Heterogeneity
Tahmini Süre:1m 30s
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Konular

Genetic and Molecular Mechanisms

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