Abstract:Background
Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare genetic disorder that is transmitted in an autosomal dominant manner with complete penetrance and variable expressivity. It is caused in 85% of the cases with a known etiology by pathogenic variants in the PTCH1 gene, and is characterized by a wide range of developmental abnormalities and a predisposition to multiple neoplasms. The manifestations are multiple and systemic and consist of basal cell ca… Show more
“… 27 Congenital cataracts are found in 18% of patients with Gorlin–Goltz syndrome, which is caused by mutations in the SHH receptor gene PTCH1 . 29 BMP4 is expressed strongly in the optic vesicle and weakly in the surrounding mesenchyme and surface ectoderm, where it has crucial roles during lens induction. 30 SHH signaling plays a key role in cataract development and in the response of normal lenses to radiation injury.…”
Purpose
To identify the genetic basis of an unusual pediatric cortical cataract demonstrating autosomal dominant inheritance in a large European–Australian pedigree.
Methods
DNA from four affected individuals were exome sequenced utilizing a NimbleGen SeqCap EZ Exome V3 kit and HiSeq 2500. DNA from 12 affected and four unaffected individuals were genotyped using Human OmniExpress-24 BeadChips. Multipoint linkage and haplotyping were performed (Superlink-Online SNP). DNA from one affected individual and his unaffected father were whole-genome sequenced on a HiSeq X Ten system. Rare small insertions/deletions and single-nucleotide variants (SNVs) were identified in the disease-linked region (Golden Helix SVS). Combined Annotation Dependent Depletion (CADD) analysis predicted variant deleteriousness. Putative enhancer function and variant effects were determined using the Dual-Glo Luciferase Assay system.
Results
Linkage mapping identified a 6.23-centimorgan support interval at chromosome 7q36. A co-segregating haplotype refined the critical region to 6.03 Mbp containing 21 protein-coding genes. Whole-genome sequencing uncovered 114 noncoding variants from which CADD predicted one was highly deleterious, a novel substitution within intron-1 of the
sonic hedgehog signaling molecule
(
SHH
) gene. ENCODE data suggested this site was a putative enhancer, subsequently confirmed by luciferase reporter assays with variant-associated gene overexpression.
Conclusions
In a large pedigree, we have identified a
SHH
intron variant that co-segregates with an unusual pediatric cortical cataract phenotype. SHH is important for lens formation, and mutations in its receptor (
PTCH1
) cause syndromic cataract. Our data implicate increased function of an enhancer important for SHH expression primarily within developing eye tissues.
“… 27 Congenital cataracts are found in 18% of patients with Gorlin–Goltz syndrome, which is caused by mutations in the SHH receptor gene PTCH1 . 29 BMP4 is expressed strongly in the optic vesicle and weakly in the surrounding mesenchyme and surface ectoderm, where it has crucial roles during lens induction. 30 SHH signaling plays a key role in cataract development and in the response of normal lenses to radiation injury.…”
Purpose
To identify the genetic basis of an unusual pediatric cortical cataract demonstrating autosomal dominant inheritance in a large European–Australian pedigree.
Methods
DNA from four affected individuals were exome sequenced utilizing a NimbleGen SeqCap EZ Exome V3 kit and HiSeq 2500. DNA from 12 affected and four unaffected individuals were genotyped using Human OmniExpress-24 BeadChips. Multipoint linkage and haplotyping were performed (Superlink-Online SNP). DNA from one affected individual and his unaffected father were whole-genome sequenced on a HiSeq X Ten system. Rare small insertions/deletions and single-nucleotide variants (SNVs) were identified in the disease-linked region (Golden Helix SVS). Combined Annotation Dependent Depletion (CADD) analysis predicted variant deleteriousness. Putative enhancer function and variant effects were determined using the Dual-Glo Luciferase Assay system.
Results
Linkage mapping identified a 6.23-centimorgan support interval at chromosome 7q36. A co-segregating haplotype refined the critical region to 6.03 Mbp containing 21 protein-coding genes. Whole-genome sequencing uncovered 114 noncoding variants from which CADD predicted one was highly deleterious, a novel substitution within intron-1 of the
sonic hedgehog signaling molecule
(
SHH
) gene. ENCODE data suggested this site was a putative enhancer, subsequently confirmed by luciferase reporter assays with variant-associated gene overexpression.
Conclusions
In a large pedigree, we have identified a
SHH
intron variant that co-segregates with an unusual pediatric cortical cataract phenotype. SHH is important for lens formation, and mutations in its receptor (
PTCH1
) cause syndromic cataract. Our data implicate increased function of an enhancer important for SHH expression primarily within developing eye tissues.
“…Neben Keratinzysten, die bisher selten im Rahmen des GGS beschrieben wurden, ist auch die Myopie typisch für das GGS [ 5 ].…”
Section: Diskussionunclassified
“…Neben einer Katarakt sind beim GGS nicht nur Kolobome an Iris, Netzhaut und Papille beschrieben, sondern auch vitreoretinale Interface-Erkrankungen, Myopie, myelinisierte Nervenfasern, Hypertelorismus sowie Strabismus mit Amblyopien, wahrscheinlich aufgrund von anatomischen Anomalien (Abb. 3 ; [ 3 , 5 ]). …”
“…14 Other common findings in NBCCS patients are hypertelorism, congenital cataract, strabismus, myelinated fibers, retinal hamartoma, optic nerve colobomas, nystagmus and palpebral ptosis. [15][16][17][18] The objective of the present study is to evaluate the integrity of the macular pathways and functionality in NBCCS patients by means of pattern reversal visual evoked potentials (pVEPs). The results obtained were compared with a control group (CG) of healthy subjects.…”
Introduction: Gorlin-Goltz syndrome (GGS) also known as nevoid basal cell carcinoma syndrome (NBCCS) is a complex rare genetic disorder characterized by a wide range of clinical and radiological manifestations. Ophthalmological alterations have always been reported, but no study on the eventual pattern visual evoked potentials (pVEPs) abnormalities has yet been published. Purpose: The purpose of the study was to evaluate the functionality of the optic pathways in a group of NBCCS patients through pattern reversal VEPs, after a thorough exclusion of subjects with preexisting ocular and optic pathways pathologies. Methods: Nineteen NBCCS patients (31 eyes) and 20 healthy controls (40 eyes) have been recruited for this study. All subjects underwent an evaluation of the functionality of the optic pathways through pVEPs with small (120ʹ), medium (60ʹ), and large (15ʹ) check size stimulation. Results: NBCCS patients showed a statistically significant alteration in the transmission of the macular pathway function when compared to controls. PVEPs analysis confirmed a reduced amplitude and an increased latency of the P100 component, suggesting an involvement of the visual pathway even in the absence of ocular clinical manifestations. Conclusion: Visual pathways may have been affected both by a subclinical myelination deficit, determined directly by the genetic alteration, as well as by neurological abnormalities typical of this syndrome. Further studies are warranted.
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