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Microduplication of 7q36.3 encompassing the SHH long?range regulator (ZRS) in a patient with triphalangeal thumb?polysyndactyly syndrome and congenital heart disease.

ABSTRACT: Triphalangeal thumb?polysyndactyly syndrome (TPT?PS) is an autosomal dominant disorder with complete penetrance and a variable expression consisting of opposable triphalangeal thumbs, duplication of the distal thumb phalanx, pre?axial polydactyly and duplication of the big toes (hallux). The causative gene of TPT?PS has been mapped to 7q36.3. Sonic hedgehog (SHH) expressed in the zone of polarizing activity (ZPA) has an important role in defining the anterior?posterior axis and numbers of digits in limb bud development. Point mutation or duplication in the ZPA regulatory sequence (ZRS), a cis?regulator of SHH, will lead to TPT?PS. The present study describes a 1?year?old female congenital heart disease (CHD) patient with TPT?PS phenotype. In this Han Chinese family with TPT?PS, high resolution single nucleotide polymorphism array technology identi?ed a novel 0.29 Mb duplication comprising ZRS at 7q36.3 where LMBR1 is located. Additionally, a novel deletion of 22q11.21 was detected in the proband with Tetralogy of Fallot. However, the parents and other relatives of the patient did not harbor this genomic lesion nor CHD. The ?ndings supported the hypothesis that an increased copy number variation of ZRS is the genetic mechanism underlying the phenotype of TPT?PS, and corroborated that 22q11.21 deletion is a genetic cause of CHD.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5364826 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Microduplication of 7q36.3 encompassing the SHH long‑range regulator (ZRS) in a patient with triphalangeal thumb‑polysyndactyly syndrome and congenital heart disease.

Liu Zhenghua Z Yin Ni N Gong Lianghui L Tan Zhiping Z Yin Bangliang B Yang Yifeng Y Luo Cheng C

Molecular medicine reports 20161229 2

Triphalangeal thumb‑polysyndactyly syndrome (TPT‑PS) is an autosomal dominant disorder with complete penetrance and a variable expression consisting of opposable triphalangeal thumbs, duplication of the distal thumb phalanx, pre‑axial polydactyly and duplication of the big toes (hallux). The causative gene of TPT‑PS has been mapped to 7q36.3. Sonic hedgehog (SHH) expressed in the zone of polarizing activity (ZPA) has an important role in defining the anterior‑posterior axis and numbers of digits ...[more]

PMID: 28035386

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Project description: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 including LMBR1, 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.

Dataset Information

Microduplication of 7q36.3 encompassing the SHH long?range regulator (ZRS) in a patient with triphalangeal thumb?polysyndactyly syndrome and congenital heart disease.

Publications

Microduplication of 7q36.3 encompassing the SHH long‑range regulator (ZRS) in a patient with triphalangeal thumb‑polysyndactyly syndrome and congenital heart disease.

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