A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report

Autor: Tatiana Pervunina, Alexey Sergushichev, Olesia Melnik, G. R. Gazizova, Elena Shagimardanova, Tatiana Loevets, Ivan A. Kozyrev, Mikhail Gordeev, Anna Kostareva, Oleg Gusev, Rostislav K. Skitchenko, Yulia Fomicheva, Tatiana Vershinina, Anna Zlotina, Elena Vasichkina
Rok vydání: 2020
Předmět:
0301 basic medicine
Proband
Male
Case Report
030105 genetics & heredity
Microphthalmia
Umbilical Arteries
Gene Duplication
Gene duplication
Microphthalmos
Genetics (clinical)
Genetics
Coloboma
Comparative Genomic Hybridization
Syndrome
Double Outlet Right Ventricle
Pedigree
Phenotype
Female
Chromosomes
Human
Pair 7
Adult
lcsh:Internal medicine
Long-range sonic hedgehog (SHH) regulator (ZRS)
lcsh:QH426-470
Optic Disk
Locus (genetics)
Polymorphism
Single Nucleotide
Congenital Abnormalities
03 medical and health sciences
Double outlet right ventricle
Triphalangeal thumb-polysyndactyly syndrome
LMBR1
medicine
Humans
Abnormalities
Multiple
Syndactyly
7q36 duplication
lcsh:RC31-1245
Anophthalmia
business.industry
Infant
Membrane Proteins
DORV
medicine.disease
lcsh:Genetics
030104 developmental biology
business
Mandibulofacial Dysostosis
Microphthalmia with coloboma
Zdroj: BMC Medical Genomics
BMC Medical Genomics, Vol 13, Iss 1, Pp 1-9 (2020)
ISSN: 1755-8794
Popis: BackgroundTriphalangeal thumb-polysyndactyly syndrome (TPT-PS) is a rare well-defined autosomal dominant disorder characterized by long thumbs with three phalanges combined with pre- and postaxial polydactyly/syndactyly of limbs. By now, the syndrome has been reported in several large families from different ethnic backgrounds, with a high degree of inter- and intrafamilial variability. The genome locus responsible for TPT-PS has been mapped to the 7q36.3 region harboring a long-range sonic hedgehog (SHH) regulatory sequence (ZRS). Both single-nucleotide variants and complete duplications of ZRS were shown to cause TPT-PS and similar limb phenotypes. TPT-PS usually forms as isolated limb pathology not associated with additional malformations, in particular, with cardiovascular abnormalities.Case presentationHere we report on a rare Russian neonatal case of TPT-PS combined with severe congenital heart disease, namely double outlet right ventricle, and microphthalmia with optic disc coloboma. Pedigree analysis revealed TPT-PS of various expressivity in 10 family members throughout five generations, while the cardiac defect and the eye pathology were detected only in the proband. To extend the knowledge on genotype–phenotype spectrum of TPT-PS, the careful clinical and genomic analysis of the family was performed. High-resolution array-based comparative genomic hybridization (array-CGH) revealed a ~ 300 kb microduplication of 7q36.3 locus (arr[GRCh37] 7q36.3(156385810_156684811) × 3) that co-segregated with TPT-PS in the proband and her mother. The duplication encompassed three genes includingLMBR1, the intron 5 of which is known to harbor ZRS. Based on whole-exome sequencing data, no additional pathogenic mutations or variants of uncertain clinical significance were found in morbid cardiac genes or genes associated with a microphthalmia/anophthalmia/coloboma spectrum of ocular malformations.ConclusionsThe results support the previous data, indicating that complete ZRS duplication underlies TPT-PS, and suggest a broader phenotypic impact of the 7q36.3 microduplication. Potential involvement of the 7q36.3 microduplication in the patient’s cardiac and eye malformations is discussed. However, the contribution of some additional genetic/epigenetic factors to the complex patient`s phenotype cannot be excluded entirely. Further comprehensive functional studies are needed to prove the possible involvement of the 7q36.3 locus in congenital heart disease and eye pathology.
Databáze: OpenAIRE
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