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Results for “Variant pathogenicity assessment”

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PubMed2026

Novel splice-site and recurrent p.Arg729* CNKSR2 variants in ESES/CSWS: insights into sex-dependent expression.

PURPOSE: Pathogenic variants in CNKSR2 (Xp22.12) cause an X-linked neurodevelopmental disorder with intellectual disability, language impairment, and a distinctive epilepsy phenotype, including encephalopathy with status epilepticus during slow-wave sleep (ESES/CSWS). Hemizygous males are typically severely affected, whereas symptomatic females remain rare and incompletely characterized. We describe two unrelated patients with de novo CNKSR2 variants to expand the mutational and sex-dependent phenotypic spectrum of this disorder. METHODS: Both patients underwent clinical, electroencephalographic, and neuroimaging evaluation. CNKSR2 variants were identified by whole exome sequencing with parental segregation, and the splice-site variant was assessed in silico (SpliceAI, MaxEntScan, Human Splicing Finder). RESULTS: Patient 1, a 17-year-old female, harbored a novel canonical splice-site variant (c.64+1G>A) in the N-terminal region and presented with a relatively mild phenotype. In silico analysis supported abolition of the canonical donor splice site. Patient 2, an 8-year-old male, carried a de novo nonsense variant (c.2185C>T, p.Arg729*) and exhibited drug-resistant ESES, autism, and severe language impairment. p.Arg729* had previously been reported in one independent male. Our case represents its second independent occurrence, a CGA>TGA transition at a CpG dinucleotide consistent with a mutational hotspot. CONCLUSION: Together, these cases expand the mutational spectrum and provide further evidence for sex-dependent phenotypic variability in CNKSR2-related epilepsy. Our observations support the hypothesis that X-chromosome inactivation may contribute to phenotypic variability in females, although XCI was not assessed here, and support inclusion of CNKSR2 in epilepsy gene panels regardless of sex.

Humans↗

PubMed1999

Implications of presenilin 1 mutations in Alzheimer's disease.

Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are the most common genetic factors underlying the development of early-onset familial Alzheimer's disease (FAD). To investigate the pathogenic mechanism of PS1 mutations linked to FAD, we established inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1(M146L or deltaexon 10) under the control of the Lac repressor. Using this inducible PS1 system, the influence of PS1 mutations on the generation of endogenous murine Abeta species was assessed using a highly sensitive immunoblotting technique. The induction of mutated PS1 resulted in an increase in the extra- and intracellular levels of two distinct Abeta species ending at residue 42, Abeta1-42 and its N-terminally truncated variant(s), Abetax-42. In addition, the intracellular generation of these Abeta42 species was completely blocked by brefeldin A. In contrast, it exhibited differential sensitivities to monensin such that there was an increased accumulation of intracellular Abetax-42 but an inhibition of intracellular Abeta1-42 generation. These data strongly suggest that Abetax-42 is generated in a proximal Golgi compartment, whereas Abeta1-42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific gamma-secretase cleavage which occurs (i) in the ER or the early Golgi apparatus prior to gamma-secretase cleavage, or (ii) in the distinct sites where Abetax-42 and Abeta1-42 are generated. To date, the site of Abeta42 generation has not been firmly established. Our data provide new information regarding the site of Abeta42 generation mediated by the FAD-linked mutant PS1.

Alzheimer Disease↗

PubMed2006

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

BACKGROUND & AIMS: Inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. METHODS: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. RESULTS: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. CONCLUSIONS: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein.

Adaptor Proteins, Signal Transducing↗

PubMed1993

Adherence and surface properties of buoyant density subpopulations of group B streptococci, type III.

From clinical isolates of group B streptococci, buoyant density subpopulations with variable amounts of type-specific polysaccharide can be derived. The ability of these subpopulations to adhere to vaginal epithelial cells and to glass was assessed by using [3H]-labeled bacteria. Subpopulations with no or minute amounts of capsule showed good adherence capacity and a hydrophobic cell surface. In contrast, a large capsule made the bacteria less adherent and rendered their surface hydrophilic. A negative cell surface charge, judged by determination of the z-potential, was directly related to the amount of capsule. Proteinase K treatment of less encapsulated variants significantly decreased the cell hydrophobicity. The ability of a GBS strain to express different surface characteristics may be a mechanism for adaptation to environmental changes, and may thereby contribute to the pathogenicity of GBS.

Bacterial Adhesion↗

PubMed2025

Federated learning for the pathogenicity annotation of genetic variants in multi-site clinical settings.

MOTIVATION: Rare diseases collectively affect 5% of the population. However, fewer than 50% of rare disease patients receive a molecular diagnosis after whole genome sequencing. Supervised machine learning is a valuable approach for the pathogenicity scoring of human genetic variants. However, existing methods are often trained on curated but limited central repositories, resulting in poor accuracy when tested on external cohorts. Yet, large collections of variants generated at hospitals and research institutions remain inaccessible to machine-learning purposes because of privacy and legal constraints. Federated learning (FL) algorithms have been recently developed enabling institutions to collaboratively train models without sharing their local datasets. RESULTS: Here, we present a proof-of-concept study evaluating the effectiveness of FL for the clinical classification of genetic variants. A comprehensive array of diverse FL strategies was assessed for coding and non-coding Single Nucleotide Variants as well as Copy Number Variants. Our results showed that federated models generally achieved comparable or superior performance to traditional centralized learning. In addition, federated models reached a robust generalization to independent sets with smaller data fractions as compared to their centralized model counterparts. Our findings support the adoption of FL to establish secure multi-institutional collaborations in human variant interpretation. AVAILABILITY AND IMPLEMENTATION: All source code required to reproduce the results presented in this article, implemented in Python, is available under the GNU General Public License v3 at https://github.com/RausellLab/FedLearnVar.

Humans↗

PubMed2005

Rapid recruitment of virus-specific CD8 T cells restructures immunodominance during protective secondary responses.

In this study we investigate the attributes of virus-specific memory CD8 T cells which most effectively control secondary infections. By rechallenging mice that had cleared primary lymphocytic choriomeningitis virus infections, we revealed that the secondary response is remarkably swift. Within 6 h following secondary infection, the production of gamma interferon becomes detectable directly ex vivo. During this protective phase of the secondary response, a very early elaboration of effector activities is preferentially exhibited by T cells specific for the viral NP396 epitope. This wave of activation contains the infection primarily before the initiation of the proliferative phase of the secondary response. Marked expansion is observed, but its magnitude differs depending on the epitope specificity of the responding cells; between 42 and 48 h following infection, approximately 70% of NP396-specific memory cells are in the S phase of the cell cycle, as assessed by bromodeoxyuridine incorporation studies. Epitope-dependent differences during the proliferative phase of the secondary response were confirmed by adoptive transfer studies with CFSE-labeled T cells. Although NP396-specific T cells typically dominate secondary responses, the broader multiepitope-specific population of antiviral T cells is beneficial for controlling a variant virus with an escape mutation in this epitope. These findings indicate that the induction and maintenance of a focused response contribute to the clearance of secondary infections; however, a more diverse pool of antiviral T cells facilitates long-term immunity to mutable pathogens.

Animals↗

PubMed1998

Familial mutations and the thermodynamic stability of the recombinant human prion protein.

Hereditary forms of human prion disease are linked to specific mutations in the PRNP gene. It has been postulated that these mutations may facilitate the pathogenic process by reducing the stability of the prion protein (PrP). To test this hypothesis, we characterized the recombinant variants of human PrP(90-231) containing point mutations corresponding to Gerstmann-Straussler-Scheinker disease (P102L), Creutzfeld-Jakob disease (E200K), and fatal familial insomnia (M129/D178N). The first two of these mutants could be recovered form from the periplasmic space of Escherichia coli in a soluble form, whereas the D178N variant aggregated into inclusion bodies. The secondary structure of the two soluble variants was essentially identical to that of the wild-type protein. The thermodynamic stability of these mutants was assessed by unfolding in guanidine hydrochloride and thermal denaturation. The stability properties of the P102L variant were indistinguishable from those of wild-type PrP, whereas the E200K mutation resulted in a very small destabilization of the protein. These data, together with the predictive analysis of other familial mutations, indicate that some hereditary forms of prion disease cannot be rationalized using the concept of mutation-induced thermodynamic destabilization of the cellular prion protein.

Creutzfeldt-Jakob Syndrome↗

PubMed2026

Escalation of CTX-M-producing extensively drug-resistant Shigella spp. in Kolkata, India, following the COVID-19 pandemic.

Shigella spp. is recognized by the World Health Organization as a high-priority pathogen due to its global prevalence, unique pathogenic mechanisms, and growing antimicrobial resistance (AMR). Nearly half of all Shigella strains worldwide are now multidrug-resistant (MDR), and the emergence of extensively drug-resistant (XDR) variants-resistant to ciprofloxacin, ceftriaxone, and azithromycin-has severely limited effective treatment options. The present study is based on prospective laboratory surveillance involving 323 Shigella isolates collected during 2021-2023, with pre-COVID-19 pandemic data included from a previously published study solely for historical comparison. The presence of antibiotic resistance genes (ARGs) was investigated, and whole-genome sequencing (WGS) was performed on representative isolates to assess phylogenetic relatedness with global isolates. Approximately 10% of isolates exhibited resistance to third-generation cephalosporins. While only 3% of Shigella isolates carried the blaCTX-M-15 gene from 2013 to 2019, its prevalence increased to 26% by 2022-2023. Among 38 ceftriaxone-resistant S. sonnei isolates, 33 were also resistant to azithromycin, categorizing them as XDR. These isolates showed 48% clonal similarity and high phylogenetic resemblance to the isolates reported from England. Hybrid genome assembly revealed a plasmid harboring both the blaCTX-M-15 and mphA ARGs. Conjugation experiments and plasmid profiling confirmed the plasmid's transferability. We report a rising trend in third-generation cephalosporin resistance among Shigella spp., primarily driven by the spread of extended-spectrum β-lactamase-producing S. flexneri and the emergence of XDR S. sonnei. These findings underscore the urgent need for strengthened national AMR containment strategies and enhanced international surveillance of cephalosporin-resistant Shigella to mitigate this growing public health threat.IMPORTANCEShigella is a leading cause of diarrheal disease globally and has been prioritized by the World Health Organization due to its rapid acquisition of antimicrobial resistance. Our prospective surveillance in Kolkata, India, reveals a worrisome escalation of third-generation cephalosporin resistance over the past decade, primarily associated with the spread of blaCTX-M-15 and the emergence of extensively drug-resistant (XDR) S. sonnei. The detection of plasmids carrying both blaCTX-M-15 and mphA, coupled with evidence of their transferability, highlights the potential for accelerated dissemination of multidrug resistance. When compared with a global data set of international genomes, the Kolkata XDR isolates were found to cluster closely with isolates reported from England. By linking local surveillance with global genomic context, our findings provide critical insights for treatment guidelines, antimicrobial stewardship, and the design of international containment strategies aimed at curbing the rise of cephalosporin- and azithromycin-resistant Shigella.

India↗

PubMed2003

Molecular analysis of the capsid coding region of a virulent encephalomyocarditis virus isolate after serial cell passages and assessment of its virulence.

EMCV has been recognized as a worldwide-shared pathogen in many host species with natural differences of virulence among strains. Differences of virulence were also demonstrated experimentally after serial passages of particular EMCV strains in cell culture. In order to evaluate the genetic variability of the CCR of an highly virulent Belgian EMCV isolate after 210 passages in cell culture, this region has been molecularly characterised by RT-PCR and sequencing. The analyses enlightened the stability of the isolate as only 3 mutations appeared within the CCR and this was observed between passage 200 and 210. One of the mutations is adjacent to the amino acid described as the differentiation amino acid between diabetogenic and non-diabetogenic variants of EMCV. An experimental inoculation of pigs with the passage 210 of the virus enlightened its attenuation and the challenged pigs were protected against the wild-type virus. Results confirm the ability of EMCV to become attenuated after passages in cell culture.

Animals↗

PubMed2026

Whole-exome sequencing-centered genetic evaluation for early-onset obesity in Chinese children: a retrospective single-center cohort.

BACKGROUND: Genetic causes of early-onset obesity remain undercharacterized in East Asian children. This study evaluated a whole-exome sequencing (WES)-centered diagnostic workflow in Chinese children with obesity onset before 5 years. METHODS: Consecutive children with body mass index above the 95th percentile and obesity onset before 5 years who completed structured inpatient assessment at a single center between February 2022 and December 2023 were retrospectively analyzed. Phenotyping included clinical, biochemical, oral glucose tolerance, cortisol rhythm, and liver assessments. Genetic testing combined WES, mitochondrial DNA analysis, multiplex ligation-dependent probe amplification (MLPA) for obesity-related imprinting loci, WES-based copy-number variant and runs-of-homozygosity analyses, and Sanger validation. Variants were interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. RESULTS: Among 23 children, clinically relevant genetic findings were identified in 6 (26.1%): melanocortin-4 receptor (MC4R) c.831T>A (p.C277*), maternal uniparental disomy of 15q11-13, and four phenotype-correlated variants of uncertain significance in UCP3, BBS1, NCOA1, and SH2B1. The definitive/likely diagnostic yield, restricted to pathogenic or confirmed imprinting findings, was 8.7% (2/23). Findings involved leptin-MC4R signaling, BBSome function, fatty-acid oxidation, and chromosomal imprinting. Genetically positive children showed numerically higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but differences were not statistically significant. BBS1 p.T374S was relatively enriched in East Asian reference data. CONCLUSIONS: A WES-centered integrated workflow detected heterogeneous genetic mechanisms in Chinese children with early-onset obesity, but variant of uncertain significance (VUS)-associated findings should be distinguished from confirmed diagnoses. Orthogonal methylation/MLPA and runs of homozygosity (ROH) analyses were necessary for imprinting diagnosis. Larger multicenter studies and functional validation are needed.

Chinese children↗

PubMed2026

DENND3-p.R534S disrupts dyadic microdomain architecture to drive potentially pro-arrhythmic calcium and electrophysiologic instability.

AIMS: Inherited ventricular arrhythmias (VAs) frequently occur in the absence of pathogenic variants in canonical ion channel genes, suggesting alternative mechanisms of electrical instability. DENND3 is a guanine nucleotide exchange factor that regulates Rab GTPase-mediated trafficking, but its role in cardiac excitation-contraction coupling and membrane microdomain organization remains undefined. METHODS AND RESULTS: We studied induced pluripotent stem cell-derived cardiomyocytes generated from a CRISPR/CAS9-engineered ultra-rare DENND3-p.R534S variant-inserted line (previously identified in an idiopathic ventricular fibrillation pedigree) and matched isogenic controls. Multielectrode array recordings, live-cell calcium imaging, super-resolution imaging using expansion microscopy, and biochemical analyses were used to assess electrical activity, calcium handling, membrane architecture, and calcium release unit organization. Potentially therapeutic studies were performed using genetic and pharmacologic inhibition of Rab11b. DENND3-p.R534S induced pluripotent stem cell-derived cardiomyocytes exhibited multicellular electrical instability characterized by increased beat-to-beat variability, arrhythmic activity, conduction slowing, and prolonged excitation-contraction delay. These abnormalities were accompanied by heterogeneous and dyssynchronous calcium cycling despite preserved expression of major calcium-handling proteins. Super-resolution imaging revealed disruption of BIN1-dependent membrane architecture and nanoscale uncoupling of Cav1.2 and RyR2. Inhibition of Rab11b restored BIN1 organization, re-established dyadic coupling, normalized calcium cycling, and improved electrical stability. CONCLUSION: These findings support a model in which altered trafficking balance contributes to disruption of membrane microdomain organization, leading to dyadic uncoupling, calcium instability, and electrical dysfunction. Modulation of the Rab11b-mediated trafficking pathway restored structural and functional abnormalities, supporting the trafficking-associated pathway as a potential therapeutic target in DENND3-associated ventricular arrhythmia.

Myocytes, Cardiac↗

PubMedDate not supplied

Assessment of the ability of ratite-origin influenza viruses to infect and produce disease in rheas and chickens.

Pathobiologic characteristics were determined for three mildly pathogenic (MP) ratite-origin avian influenza viruses (AIVs). Ratite-origin AIVs produced respiratory disease in rheas, and virus was reisolated from oropharyngeal and cloacal swabs on days 2-6 postinoculation. Inoculation of two ratite-origin AIVs in the upper respiratory tract of chickens resulted in viral infections, but the mean chicken infectious dose (CID50) for A/emu/Texas/39924/93 (H5N2) (Emu/Texas) virus was 500-fold lower than the CID50 for the A/rhea/North Carolina/39482/93 (H7N1) virus. In ovo and in vivo passage of the MP parent Emu/Texas isolate resulted in emergence of a highly pathogenic (HP) variant that had high plaquing efficiency in chicken embryo fibroblast cultures and was highly lethal in chicken pathotyping tests. This variant virus produced gross lesions in chickens similar to those reported for other HP AIVs. These findings demonstrated that ratite-origin AIVs can produce significant clinical disease in rheas and have a realistic potential for interspecies transmission to domestic poultry. Furthermore, HP variants can emerge from MP H5 ratite-origin AIVs if introduced and allowed to circulate in chicken populations.

Animals↗

PubMed2000

Type- and subtype-specific RT-PCR assays for avian influenza A viruses (AIV).

Reverse transcriptase (RT) PCR assays have been developed to improve the diagnosis of avian influenza A. RT-PCR using primers complementary to a conserved region of the matrix protein was assessed as being suitable for the detection of influenza A virus RNA from poultry as well as from pigs, horses and humans, regardless of the haemagglutinin (HA) and neuraminidase (NA) subtype. Therefore, this RT-PCR is a valuable tool to confirm the initial diagnosis of any influenza A infection. As a second approach, experiments were performed to identify the HA gene encoding the post-translational cleavage site of potentially highly pathogenic AIV isolates by RT-PCR. The principal aim was to design one universal primer pair for each virus subtype, H5 and H7, respectively, which allows the detection of all strain variants using only one consistent method. To realize this objective, it was necessary to develop 'wobble' primers. AIV RNAs from seven H5 and 11 H7 subtype viruses included in the investigations were specifically recognized by RT-PCR using these primers. This method therefore provides a rapid, subtype-specific diagnosis and subsequent sequencing of H5 and H7 avian influenza viruses.

Animals↗

PubMed2026

A novel deep intronic EIF2AK3 variant disrupts splicing and causes Wolcott-Rallison syndrome.

AIM: Deep intronic variants can disrupt splicing and cause monogenic disease but are missed by routine genetic testing. This study assessed the contribution of deep intronic variants to Wolcott-Rallison syndrome (WRS), a recessive disorder characterized by early-onset diabetes and progressive multisystem disease caused by loss-of-function EIF2AK3 variants. METHODS: We investigated a cohort of 116 individuals referred to the Exeter Genomics Laboratory for genetic testing who had diabetes diagnosed at ≤2 years and at least one additional feature consistent with WRS: hepatic dysfunction, skeletal abnormalities or developmental delay. No genetic cause had been identified after testing all known early-onset diabetes genes. We screened genome-sequencing data for rare homozygous intronic EIF2AK3 variants. Candidate variants predicted to affect splicing by SpliceAI were assessed using a minigene exon-trapping assay. RESULTS: We identified two rare homozygous intronic EIF2AK3 variants in two siblings. Only one variant, c.1651-180G>T, was predicted to disrupt splicing in silico. The two children, born to consanguineous parents, were diagnosed with early-onset diabetes (diagnosed at 1 year and 21 weeks), hepatic dysfunction, skeletal abnormalities, developmental delay, thyroid dysfunction, hip dysplasia and gait abnormalities. The minigene assay showed that c.1651-180G>T creates a cryptic donor splice site within intron 9, resulting in inclusion of a 79-nucleotide pseudoexon, causing a frameshift and premature stop codon. Using this evidence, the variant was reclassified as likely pathogenic according to ACMG/ACGS guidelines. CONCLUSIONS: We report the first deep intronic EIF2AK3 variant causing WRS, highlighting the need to consider systematic intronic analysis in unresolved cases.

EIF2AK3↗

PubMed2026

Somatic-only SDHD variant with tumor-specific loss of heterozygosity in metastatic carotid body tumor: a case report with review of literature.

Carotid body tumors (CBTs) are rare paragangliomas in which genetic predisposition, particularly pathogenic variants in succinate dehydrogenase (SDHx) genes, plays an important role in tumorigenesis. Previous genetic studies of CBTs have primarily focused on germline SDHx variants, whereas somatic alterations remain poorly characterized. Among SDHx genes, SDHB variants are known to be associated with a higher metastatic risk, while SDHD variants are generally linked to a lower metastatic rate. We report the case of a 41-year-old man who presented with a painless right-sided neck mass. Imaging studies demonstrated a hypervascular tumor located at the carotid bifurcation with circumferential encasement of the carotid artery. During surgery, the tumor was classified as a Shamblin type III CBT, and complete surgical resection with vascular reconstruction was performed. Histopathological examination confirmed paraganglioma with metastasis to a single cervical lymph node. Germline genetic testing did not reveal any pathogenic variants. However, comprehensive tumor genomic profiling identified a somatic SDHD c.304C>G (p.His102Asp) variant accompanied by tumor-specific loss of heterozygosity (LOH) and copy-number loss at the SDHD locus, findings compatible with biallelic SDHD inactivation. The patient remained free of recurrence during follow-up. To our knowledge, this represents the first reported case of metastatic CBT harboring a somatic-only SDHD variant with tumor-specific LOH. This case suggests that reliance on germline testing alone may underestimate the molecular drivers of CBT and highlights the potential clinical value of tumor-based genomic profiling for risk stratification and prognostic assessment.

Carotid body tumor↗

PubMed2005

Multiple-locus variable number tandem repeats analysis for genetic fingerprinting of pathogenic bacteria.

DNA fingerprinting has attracted considerable interest as means for identifying, tracing and preventing the dissemination of infectious agents. Various methods have been developed for typing of pathogenic bacteria, which differ in discriminative power, reproducibility and ease of interpretation. During recent years a typing method, which uses the information provided by whole genome sequencing of bacterial species, has gained increased attention. Short sequence repeat (SSR) motifs are known to undergo frequent variation in the number of repeated units through cellular mechanisms most commonly active during chromosome replication. A class of SSRs, named variable number of tandem repeats (VNTRs), has proven to be a suitable target for assessing genetic polymorphisms within bacterial species. This review attempts to give an overview of bacterial agents where VNTR-based typing, or multiple-locus variant-repeat analysis (MLVA) has been developed for typing purposes, together with addressing advantages and drawbacks associated with the use of tandem repeated DNA motifs as targets for bacterial typing and identification.

Bacillus anthracis↗

PubMed2026

Genomic Profiling of Anophthalmia/Microphthalmia-Associated CNVs Reveals Complex Genotype-Phenotype Correlations and Incomplete Penetrance.

BACKGROUND: Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS: Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS: An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION: Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.

Female↗

PubMed2002

Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv/iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

Axonemal Dyneins↗