Clinical Genetics最新文献

Copy number variations (CNVs) affecting the imprinted regions in 11p15.5 (imprinting centre 1 and 2/IC1, IC2) account for more than 2% of the molecular disturbances in Beckwith-Wiedemann and Silver-Russell syndrome (BWS, SRS) and are associated with a recurrence probability of up to 50%. However, their clinical impact can be challenging to estimate, as it depends on the type of imbalance, the parental origin of the affected allele, its size and genomic content. As a result, a genotype-phenotype correlation of 11p15.5 alterations is still missing, at least for CNVs affecting only parts of the IC1 or IC2. By comprehensively summarising all published CNVs within 11p15.5 and the available clinical data of their carriers, we aim to further delineate a correlation of these disturbances with BWS and SRS features. In fact, consistent correlations could be delineated only for duplications including either both the telomeric and centromeric regions or complete gains of one of them. In contrast, CNVs encompassing only parts of these regions lead to heterogeneous phenotypes. In summary, our literature review provides support for pathogenicity assessment of CNVs in 11p15.5 as basis for genetic counselling. However, this dataset underlines the need for further research to enlighten the molecular complexity of this region and to better understand the regulation of genomic imprinting mechanisms in 11p15.5.

This schematic illustrates the genetic, molecular, and clinical consequences of ESAM loss-of-function variants identified in two unrelated Turkish families. Family 1 harbors a splice-site variant (c.451 + 5G>C) predicted to cause aberrant splicing between exons 3 and 4, leading to defective mRNA processing and loss of functional ESAM protein. Family 2 carries a nonsense variant (c.605 T>G; p.Leu202Ter) that introduces a premature stop codon within the second immunoglobulin-like domain, resulting in a truncated protein and expected nonsense-mediated mRNA decay (NMD). Both variants abolish ESAM's membrane anchoring and disrupt endothelial junctional cohesion. Clinically, affected individuals present with a distinct neurovascular phenotype characterized by intrauterine or perinatal intracranial hemorrhage, ventriculomegaly, microcephaly, spastic quadriparesis, and congenital cataracts. The lower panel summarizes the pathophysiological cascade: (1) hemorrhagic stroke resulting from vascular fragility, (2) blood-brain barrier (BBB) disruption due to tight junction dysfunction and increased transcytosis, and (3) impaired vascular network formation caused by defective endothelial tubulogenesis. Collectively, these findings establish ESAM deficiency as a congenital tight-junctionopathy linking molecular endothelial defects to severe neurodevelopmental impairment.

This study aimed to characterize the spectrum of germline pathogenic and likely pathogenic variants in cancer susceptibility genes among Uruguayan patients with breast, ovarian, or prostate cancer (BC, OvC, PCa) who self-funded multigene panel testing. We analyzed 119 unrelated adults (93 bc, 12 OvC, 14 PCa) who underwent clinical germline testing using commercially available next-generation sequencing panels (comprising both a 26 gene hereditary breast/ovarian subset and a comprehensive 85/90 gene panel). Variant classification followed international guidelines. Detection rates were calculated with 95% exact binomial confidence intervals. OvC and PCa cases were analyzed separately due to small sample sizes (n < 15). PGVs were found in 16/119 patients (13.4%): 10.8% in BC (10/93), 25% in OvC (3/12), and 21.4% in PCa (3/14). BRCA1/2 variants accounted for 25% of positive cases, while 61.5% involved non-BRCA genes (ATM, RAD51C, MUTYH). No recurrent founder mutations were detected, although MUTYH c.452A>G was observed in multiple unrelated individuals. Variants of uncertain significance were identified in 57% of BC patients (53/93), mostly missense variants in DNA repair genes. The mean age at diagnosis among PGV carriers was 50 years (range 32-66). The germline mutational spectrum in Uruguayan cancer patients is diverse. Most PGVs were found in genes other than BRCA1/2, supporting the use of MGPT for cancer risk assessment. Genetic testing should be considered for all cancer patients in Uruguay, regardless of ancestry or tumor type. Further research is needed to better understand the role of less-characterized genes in BC, OvC, and PCa predisposition.

The cleavage and polyadenylation specific factor 1 (CPSF1) gene encodes a subunit of the cleavage and polyadenylation specificity factor (CPSF), a multi-protein complex essential for mRNA 3' end processing. The role of CPSF1 in retinal function and eye development has been demonstrated using zebrafish models and heterozygous variants in CPSF1 have been reported in early-onset high myopia (MIM: 618827). Here, we present a patient with bilateral congenital cataracts and intellectual disability with a novel homozygous missense variant (c.3817G>C; p.Asp1273His) in CPSF1. This amino acid change is predicted to change the protein structure with likely damaging effect. Proteomic results in white blood cells revealed increased CPSF1 protein abundance and dysregulated proteins in pathways linked to cellular signalling processes, protein degradation, and exosome biology. To our knowledge, this is the first report of recessive CPSF1-related disease in humans presenting as a case with congenital cataracts, intellectual disability, and hyperphagia.

The mechanisms by which the autosomal dominant disorder tuberous sclerosis complex (TSC) results in liver fibrosis remain poorly understood. KDM6A, a histone demethylase, has been implicated in the pathogenesis of fibrosis in multiple tissues. This study aimed to elucidate the molecular mechanism by which KDM6A contributed to TSC-associated fibrosis. We observed fibrogenesis, epithelial-mesenchymal transition (EMT) induction and upregulation of Kdm6a in vivo and in vitro upon Tsc1 or Tsc2 deficiency. Knockdown of Kdm6a attenuated both fibrosis and EMT phenotypes. Mechanistically, Kdm6a depletion reduced phosphorylation of ERK1/2 and downregulated Snai1 expression. Activation of the MAPK/ERK pathway with PMA restored EMT-related protein expression, confirming the functional involvement of this signaling axis. Furthermore, Tsc1 or Tsc2 deficiency promoted Kdm6a expression via the mTORC1 pathway, while Kdm6a knockdown conversely suppressed mTORC1 activity by reducing mTOR protein expression, suggesting a positive feedback loop between Kdm6a expression and mTORC1. These findings indicate that Kdm6a promotes fibrosis in TSC through the activation of the MAPK/ERK/SNAI1 signaling pathway. Moreover, the combination of mTORC1 and KDM6A inhibitors results in marked regression of fibrosis and liver lesions in TSC models, unveiling a potential treatment for TSC patients with inadequate response to mTORC1 inhibitors.

Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant disorder characterized by non-scarring alopecia, skin and mucosal lesions, and keratitis. Autosomal dominant SREBF1-related Ichthyosis Follicularis, Atrichia, Photophobia (IFAP) syndrome is another rare, similar disorder. Both are now known to be caused by the same NM_004176.5(SREBF1):c.1579C>T variant, but were previously described as separate disorders. Here, we describe a case series of four novel patients that we diagnosed with SREBF1-related IFAP due to the NM_004176.5(SREBF1):c.1579C>T variant. We also performed a literature review and applied the ClinGen Lumping and Splitting criteria to these two disorders. Three of our four patients had significant gastrointestinal manifestations including gastroesophageal reflux disease and esophageal strictures/webs. To date, no gastrointestinal manifestations have been described in SREBF1-related IFAP. There are, however, multiple reports of these manifestations in cases of HMD. Applying the ClinGen Lumping and Splitting criteria demonstrated that these two previously distinct disorders are actually favored to be "lumped" into one. Taken together, a documented overlap in clinical features, the shared variant, and the gastrointestinal manifestations of our SREBF1-related IFAP patients provide evidence that HMD and SREBF1-related IFAP better represent variable expressivity of the same disorder. We propose using the unifying name of "SREBF1-syndromic epidermal differentiation disorder" (SREBF1-sEDD).

Protein truncation mutations in the gene for XPG nuclease cause a very severe clinical phenotype. Two siblings have splicing mutations, which result in in-frame deletions and a less severe phenotype.

Retinol dehydrogenases (RDHs) catalyze multiple steps in the visual cycle to regenerate 11-cis-retinal, a critical component in rod phototransduction. The structural homology between RDHs enables functional redundancy; yet Mendelian disorders are linked to RDHs. Variants in RDH12 and RDH5 cause non-syndromic inherited retinal dystrophy (IRD), whilst variants in RDH11 cause syndromic IRD. RDH11 is a minor isoenzyme catalyzing two reactions: (i) reduction of all-trans-retinal in rod photoreceptors alongside RDH12 and RDH8, and (ii) oxidation of 11-cis-retinol in the retinal pigment epithelium (RPE) alongside RDH5 and RDH10. Prior cases with RDH11 demonstrated a generalized photoreceptor dystrophy, similar to RDH12-retinopathy. We describe a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly and a novel IRD. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram implying sub-optimal oxidation of 11-cis-retinol. These features are reminiscent of RDH5-retinopathy but milder. We termed this phenotype Retinal pigment Epitheliopathy due to Sub-Optimal Recycling of Vitamin A (RESORVA). We propose that the divergence in retinal phenotypes among RDH11 cases is likely due to variant-specific protein effects on paralogous gene functioning, such as differences in activation of transcriptional adaptation.

We chronicle the diagnostic journey of a young patient suffering from severe arrhythmias and left ventricular hypertrophy, for which, after about 15 years of inconclusive genetic testing, a definitive diagnosis was made possible by finding an undescribed homozygous variant in POPDC2, a gene recently associated with CCDs and HCM.