Report of two cousins who cultivated phenotypic traits and genetic variability: the importance of genotype-phenotype adaptation

*Correspondence: [e-mail].

Abstract

Case Presentation: An 8 years-old boy, with no gestational or perinatal complications, presenting developmental delay, nystagmus, facial dysmorphia, hypotonia, hypotonia, joint hypermobility, patellar luxation, cryptorchidism and hypothyroidism. The genome sequencing revealed a likely pathogenic variant c.3842_3843del:p. (Val1281Alafs*22) in the KAT6B gene, in heterozygosis, associated to Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome, both with autosomal dominant inheritance pattern. Girl, 16 years old, paternal cousin of the firt case, presenting consanguinity (first cousin parents with paternal and maternal grandparents monozygotic twin brothers) with no gestational or perinatal complications presenting developmental delay, nystagmus, facials dysmorphias, hypotonia, low visual acuity, ataxic gait, alopecia, finger syndactyly and patellar luxation. In the genome was found a pathogenic variant c.830del:p (Gly277AlafsTer20), residing in the CDH3 gene, in homozygosity; and another probably pathogenic variant c.3379A>T:p.(Lys1127Ter) in the PRX gene, in homozygosity. The CHD3 gene is associated with the phenotypes of Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy (DEEDM) and Congenital Hypertrichosis with Juvenile Macular Dystrophy (HCDM), both with recessive autosomal inheritance; while the PRX gene is related with the phenotypes of Charcot-Marie-Tooth Disease 4F type, of autosomal recessive inheritance, and of Dejerine-Sottas Disease of autosomal dominant or recessive inheritance.

Discussion: Diseases associated with the genes reported in the diagnostic analysis of these cousins are rare, with an estimated global prevalence of <1/1,000,000. The increase in the frequency of autosomal recessive diseases caused by consanguinity is due to the finding of rare variants in alleles inherited from a common ancestor. The identification in homozygosis, in two genes reinforce the parental relationship of parents. In the grisl’s case it can be observed that the characteristics of the complex phenotype correspond to alterations in two distinct genes. However, characteristics often shared by members of the same family need to be better investigated by molecular genetic tests.

Final Comments: The described individuals, despite sharing important family consanguinity, as well as some phenotypic characteristics suggesting involvement of one or more genes segregating in the family, have distinct molecular diagnosis.

Publication History

Article published online:
12 May 2025