We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype.
Case series.
A cohort of ...217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls.
High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography.
Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings.
Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions.
This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population.
Abstract
Transducin β-like 1 X-linked (TBL1X) gene encodes a subunit of the nuclear corepressor-silencing mediator for retinoid and thyroid hormone receptor complex (NCoR-SMRT) involved in repression ...of thyroid hormone action in the pituitary and hypothalamus. TBL1X defects were recently associated with central hypothyroidism and hearing loss. The current study aims to describe the clinical and genetic characterization of a male diagnosed with central hypothyroidism through thyroid hormone profiling, TRH test, brain MRI, audiometry, and psychological evaluation. Next-generation sequencing of known genes involved in thyroid disorders was implemented. The 6-year-old boy was diagnosed with central hypothyroidism free T4: 10.42 pmol/L (normal: 12 to 22 pmol/L); TSH: 1.57 mIU/L (normal: 0.7 to 5.7 mIU/L), with a mildly reduced TSH response to TRH. He was further diagnosed with attention-deficit/hyperactivity disorder (ADHD) at 7 years, alternating episodes of encopresis and constipation, and frequent headaches. MRI showed a normal pituitary but detected a Chiari malformation type I (CMI). At 10 years, audiometry identified poor hearing threshold at high frequencies. Sequencing revealed a nonsense hemizygous mutation in TBL1X c.1015C>T; p.(Arg339Ter) largely truncating its WD-40 repeat domain involved in nuclear protein-protein interactions. In conclusion, to our knowledge, we identified the first severely truncating TBL1X mutation in a patient with central hypothyroidism, hypoacusia, and novel clinical features like ADHD, gastrointestinal dysmotility, and CMI. Given the relevance of TBL1X and NCoR-SMRT for the regulation of transcriptional programs at different tissues (pituitary, cochlea, brain, fossa posterior, and cerebellum), severe mutations in TBL1X may lead to a distinct syndrome with a phenotypic spectrum wider than previously reported.
Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain ...unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes.
Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored.
We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio HR, 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers.
g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.
Glucogenosis type IX is caused by pathogenic variants of the PHKA2 gene. Herein, we report a patient with clinical symptoms compatible with Glycogen Storage Disease type IXa. PYGL, PHKA1, PHKA2, PHKB ...and PHKG2 genes were analyzed by Next Generation Sequencing (NGS). We identified the previously undescribed hemizygous missense variant NM_000292.2(PHKA2):c.1963G>A, p.(Glu655Lys) in PHKA2 exon 18. In silico analyses showed two possible pathogenic consequences: it affects a highly conserved amino acid and disrupts the exon 18 canonical splice donor site. The variant was found as a “de novo” event.
Several mutations have been described in the RDH12 gene that disturb the activity of the encoded protein, suggesting that RDH12 loss of function disrupts the synthetic pathway of the visual ...chromophore 11-cis-retinal, therefore resulting in early and progressive retinal degeneration (RD). Mutations in this gene have been related to autosomal recessive Leber congenital amaurosis (LCA) and to a form of autosomal recessive childhood-onset severe retinal dystrophy (CSRD). This study was undertaken to attempt to correlate the genotype and phenotype in Spanish CSRD and LCA patients who harbor RDH12 mutations.
A complete ophthalmic and electrophysiologic examination was performed according to preexisting protocols. A screening for mutations was then performed using denaturing HPLC on a DNA fragment analysis system. Those fragments bearing an abnormal pattern were sequenced.
Ten families bearing RDH12 mutations in homozygous or compound heterozygous form were found. All of them corresponded to patients with severe and early-onset retinal dystrophy.
The RDH12-associated phenotype is not homogeneous, the position and nature of the mutations clearly influence the pathologic expression of this disease.
Electromyography showed myopathic pattern, muscle biopsy, a dystrophic pattern, and the immunohistochemical analysis showed a lower intensity of staining with anti-DYS-3 antibody (Dp427m-dystrophin ...protein) Figure 1a.{Figure 1} These results focused the diagnosis on the Becker muscular dystrophy (BMD), and treatment with corticosteroids was indicated. No point mutations in the DMD gene were found and 23 genes associated with LGMD and Emery-Dreifuss muscular dystrophy were analyzed: Both mutations in the CAPN3 gene cause a change in...
Non-syndromic pediatric cataracts are defined as opacification of the crystalline lens that occurs during the first years of life without affecting other organs. Given that this disease is one of the ...most frequent causes of reversible blindness in childhood, the main objective of this study was to propose new responsible gene candidates that would allow a more targeted genetic approach and expand our genetic knowledge about the disease. We present a whole exome sequencing (WES) study of 20 Spanish families with non-syndromic pediatric cataracts and a previous negative result on an ophthalmology next-generation sequencing panel. After ophthalmological evaluation and collection of peripheral blood samples from these families, WES was performed. We were able to reach a genetic diagnosis in 10% of the families analyzed and found genes that could cause pediatric cataracts in 35% of the cohort. Of the variants found, 18.2% were classified as pathogenic, 9% as likely pathogenic, and 72.8% as variants of uncertain significance. However, we did not find conclusive results in 55% of the families studied, which suggests further studies are needed. The results of this WES study allow us to propose
,
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,
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,
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as potential candidates to further investigate for their role in pediatric cataracts, and
and locus 2q37 as causal genes.
CLAPO syndrome is a rare vascular disorder characterized by capillary malformation of the lower lip, lymphatic malformation predominant on the face and neck, asymmetry, and partial/generalized ...overgrowth. Here we tested the hypothesis that, although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.
We clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from 9 patients using high-throughput, deep sequencing.
We identified five activating mutations in the PIK3CA gene in affected tissues from 6 of the 9 patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.
We describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.
Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our ...main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.
Purpose
To describe and analyze the biomicroscopic features and in vivo confocal microscopy of the crystalline form of pre-Descemet corneal dystrophy (PDCD).
Methods
We examined two non-related ...families using biomicroscopy, in vivo confocal microscopy, and a genetic study using a gene panel test, looking for mutations in the
PIKFYVE
gene.
Results
A slit-lamp examination of the first family revealed polychromatic crystalline punctiform opacities distributed all over the stroma in 8 of 11 family members in three generations with an autosomal dominant inheritance. The second family showed in three of four members in two generations the same opacities located in the pre-Descemet region. It was also a hint for autosomal dominant inheritance. The in vivo confocal microscopy identified numerous rounded and hyperreflective stromal particles measuring 10–15 μm in diameter, with the highest density in the posterior stroma and with normal keratocytes. No systemic disease was diagnosed. No variants or mutations were identified in
PIKFYVE
gene.
Conclusions
Polychromatic deposits in patients with Punctiform and Polychromatic Pre-Descemet corneal dystrophy can be located not only in the deep stroma but also in the anterior and middle stroma. Our presentation reveals the possibility of considering this characteristic corneal disorder as a corneal dystrophy of its own and not as a subtype of pre-Descemet corneal dystrophy.
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