Biomedical subjects

Eric W Klee

Publications and source records attributed to Eric W Klee.

6 recordsLinked to original sources

PubMed2026

A Novel De Novo STAG1 Variant at the RAD21 Binding Interface Is Associated With Hypoglycemia, Recurrent Fever, Immunodeficiency and Features of Classical Cohesinopathies.

The cohesin complex, composed of SMC1, SMC3, RAD21, and STAG1/STAG2, is essential for chromosome cohesion, DNA repair, and transcriptional regulation. Pathogenic variants in cohesin components cause cohesinopathies. The classical characteristics of cohesinopathies include developmental delay (DD), intellectual disability (ID), feeding difficulties, hypotonia, short stature, hearing loss, and dysmorphic features. Here, we present a 5-year-old boy with classical cohesinopathy features, including DD/ID and feeding difficulties, along with non-classical features such as hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a novel de novo missense variant of uncertain significance (NM_005862.3:c.643G>A(p.Val215Ile)) in the STAG1 gene. The variant localizes to the RAD21 interaction interface, and molecular dynamics (MD) simulations revealed conformational changes comparable to other STAG1 variants reported as likely pathogenic in patients, supporting a deleterious effect which may disrupt the STAG1-RAD21 interaction interface. This case expands the phenotypic and molecular spectrum of STAG1-related cohesinopathy and advances our understanding of the disease mechanism.

STAG1↗

PubMed2026

A Second Report of a Missense Variant in AMMECR1 Causing Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis: Case Report and Literature Review.

Pathogenic variants in AMMECR1 have been associated with a rare multisystem disorder characterized by midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN). To date, most reported cases involve copy number variants or presumed loss-of-function alterations, with only a single prior report describing a missense variant supported by functional studies. Here, we report a patient with a heterozygous de novo AMMECR1 missense variant, NM_015365.3:c.649G>A p.(Val217Met) presenting with clinical features consistent with MFHIEN, including midface hypoplasia, partial hearing impairment, nephrocalcinosis, and elliptocytosis identified on peripheral blood smear. Comparative review of the literature highlights that while previously reported missense variants in AMMECR1 demonstrated altered intranuclear protein distribution and reduced expression in functional assays, clinical evidence supporting pathogenicity of non-truncating variants remains limited. The phenotypic overlap between our patient and prior report strengthens the association between missense variations and the MFHIEN phenotype. Our findings support the pathogenic relevance of missense variation in AMMECR1 and emphasize the importance of integrating detailed phenotyping, including hematologic evaluation, with genomic data in the diagnosis of rare multisystem disorders. Additional cases and functional studies are needed to clarify genotype-phenotype correlations and underlying disease mechanisms.

Humans↗

PubMed2026

Clinical and genetic characterization of constitutional MLH1 promoter hypermethylation: Implications for Lynch syndrome diagnosis.

PURPOSE: Constitutional MLH1 promoter hypermethylation (CMPH) is a relatively rare cause of Lynch syndrome. While most cases appear to be sporadic, some result from secondary epimutations, mainly caused by germline variants in the MLH1 promoter region. This study describes the clinical phenotype and genetic etiology of CMPH in the largest clinical cohort to date. METHODS: A retrospective analysis was conducted for 422 individuals who underwent clinical CMPH testing. Promoter sequencing was used to identify the underlying variants. Long-read sequencing further characterized MLH1 promoter methylation. RESULTS: CMPH was identified in 15.6% of the study cohort participants. Of these, 63 exhibited clinical features consistent with Lynch syndrome. The most common associated cancers were colorectal cancer, followed by endometrial cancer, breast cancer, and sebaceous neoplasms. Mendelian inheritance of CMPH was observed in 5 families in the study cohort, indicating secondary epimutations. Promoter sequencing identified 8 unique germline variants, including 3 novel variants. Methylation analysis by long-read sequencing revealed mutant allele-specific promoter methylation for these variants. CONCLUSION: Our findings provide the most comprehensive review of the clinical phenotype associated with CMPH and highlight the significant contribution of promoter variants to its etiology. These results underscore the need to include the assessment of constitutional MLH1 promoter methylation for Lynch syndrome diagnosis.

Humans↗

PubMed2025

Rethinking the pathogenicity of intragenic DMD duplications detected by carrier screening: High prevalence of nontandem duplications revealed by long-read sequencing.

PURPOSE: The pathogenicity of intragenic duplications depends on their structural configuration. Tandem duplications often disrupt reading frames and cause gene loss of function, whereas interspersed (nontandem) duplications are largely benign. When the configuration cannot be determined, current guidelines presume a tandem structure, leading to some laboratories automatically classifying such variants as likely pathogenic or pathogenic. This study evaluates the validity of this presumption for DMD, in patients with and without clinical indications of dystrophinopathy. METHODS: We performed high-coverage long-read genome sequencing on 15 patients with intragenic DMD duplications. A total of 4 patients had clinically indicated dystrophinopathy testing, whereas in the remaining 11 patients, the duplications were detected without clear indications of dystrophinopathy (eg, through carrier screening). RESULTS: All 4 patients with clinical indications had tandem duplications. In contrast, 64% (7/11) of the cases without such indications had interspersed duplications, with 4 subsequently reclassified as likely benign, 2 (likely) pathogenic, and 1 uncertain. These duplications were often complex, involving coduplications or codeletions with other regions. CONCLUSION: Our findings challenge the presumption that intragenic DMD duplications are predominantly in tandem. This highlights the need for a cautious variant interpretation approach, particularly in carrier screening and other settings in which variants are identified without indications of dystrophinopathy.

Humans↗

PubMed2025

A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1.

BACKGROUND: NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1. CASE PRESENTATION: The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant's effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic. CONCLUSIONS: We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development.

Humans↗

PubMed2025

Discovery of a MET -driven monogenic cause of steatotic liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction-associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking. APPROACH AND RESULTS: We identified a novel genetic variant in a familial case of metabolic dysfunction-associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. CONCLUSIONS: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.

Adult↗