Heterozygous Variants Research Articles

A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis.

DICER1 syndrome is an autosomal-dominant disorder that results in malignant or benign tumors. A number of distinct pathogenic germline and somatic variants have been identified as causing multinodular goiter (MNG). The purpose of the present study was to identify and characterize the genetic cause underlying the familial form of MNG through a whole-exome sequencing (WES) analysis in an Argentine family with three affected siblings. Clinical, biochemical and molecular genetics as well as bioinformatics analysis were performed. A novel heterozygous variant in the DICER1 gene was identified in the proband patient by WES. The variant was a single guanine deletion at nucleotide position 2,042 (NM_177438.3:c.2042del) resulting in a frameshift at amino acid 681 with a putative premature stop codon [NP_803187.1:p.Gly681ValfsTer4]. Family segregation analysis showed that his affected sister and his affected brother also were heterozygous for same variant, whereas the father was a healthy heterozygous carrier of the variant and the healthy mother harbor only wild-type alleles in the DICER1 gene. We have also observed that the frameshift variant does not interfere with the pre-mRNA splicing of the exon 13. In addition, two clinically relevant heterozygous variants, not associated with thyroid disease, were also identified in index sibling using the Franklin platform, a frameshift [NP_000234.1:p.Thr55AsnfsTer49] in the MEFV gene (familial mediterranean fever) and a missense [NP_004530.1:p.Ala422Thr] in the NARS1 gene (neurodevelopmental delay and ataxia). In conclusion, in the present study we have identified a novel frameshift variant corresponding to NP_803187.1:p.Gly681ValfsTer4 in the DUF 283 domain of DICER1. The results were in accordance with previous observations confirming the genetic heterogeneity of DICER1 syndrome. Moreover, the identification of this variant in the unaffected father substantiates the hypothesis of incomplete/reduced penetrance.

Autism-Linked Mutations in α2δ-1 and α2δ-3 Reduce Protein Membrane Expression but Affect Neither Calcium Channels nor Trans-Synaptic Signaling

Background: α2δ proteins regulate membrane trafficking and biophysical properties of voltage-gated calcium channels. Moreover, they modulate axonal wiring, synapse formation, and trans-synaptic signaling. Several rare missense variants in CACNA2D1 (coding for α2δ-1) and CACNA2D3 (coding for α2δ-3) genes were identified in patients with autism spectrum disorder (ASD). However, the pathogenicity of these variants is not known, and the molecular mechanism by which α2δ proteins may contribute to the pathophysiology of autism is, as of today, not understood. Therefore, in this study we functionally characterized two heterozygous missense variants in α2δ-1 (p.R351T) and α2δ-3 (p.A275T), previously identified in patients with ASD. Methods: Electrophysiological recordings in transfected tsA201 cells were used to study specific channel-dependent functions of mutated α2δ proteins. Membrane expression, presynaptic targeting, and trans-synaptic signaling of mutated α2δ proteins were studied upon expression in murine cultured hippocampal neurons. Results: Homologous expression of both mutated α2δ proteins revealed a strongly reduced membrane expression and synaptic localization compared to the corresponding wild type α2δ proteins. Moreover, the A275T mutation in α2δ-3 resulted in an altered glycosylation pattern upon heterologous expression. However, neither of the mutations compromised the biophysical properties of postsynaptic L-type (CaV1.2 and CaV1.3) and presynaptic P/Q-type (CaV2.1) channels when co-expressed in tsA201 cells. Furthermore, presynaptic expression of p.R351T in the α2δ-1 splice variant lacking exon 23 did not affect trans-synaptic signaling to postsynaptic GABAA receptors. Conclusions: Our data provide evidence that the pathophysiological mechanisms of ASD-causing mutations of α2δ proteins may not involve their classical channel-dependent and trans-synaptic functions. Alternatively, these mutations may induce subtle changes in synapse formation or neuronal network function, highlighting the need for future α2δ protein-linked disease models.

Phasing Nanopore genome assembly by integrating heterozygous variations and Hi-C data.

Haplotype-resolved genome assemblies serve as vital resources in various research domains, including genomics, medicine, and pangenomics. Algorithms employing Hi-C data to generate haplotype-resolved assemblies are particularly advantageous due to its ready availability. Existing methods primarily depend on mapping quality to filter out uninformative Hi-C alignments which may be susceptible to sequencing errors. Setting a high mapping quality threshold filters out numerous informative Hi-C alignments, whereas a low mapping quality threshold compromises the accuracy of Hi-C alignments. Maintaining high accuracy while retaining a maximum number of Hi-C alignments can be challenging. In our experiments, heterozygous variations play an important role in filtering uninformative Hi-C alignments. Here, we introduce Diphase, a novel phasing tool that harnesses heterozygous variations to accurately identify the informative Hi-C alignments for phasing and to extend primary/alternate assemblies. Diphase leverages mapping quality and heterozygous variations to filter uninformative Hi-C alignments, thereby enhancing the accuracy of phasing and the detection of switches. To validate its performance, we conducted a comparative analysis of Diphase, FALCON-Phase, and GFAse on various human datasets. The results demonstrate that Diphase achieves a longer phased block N50 and exhibits higher phasing accuracy while maintaining a lower hamming error rate. The source code of Diphase is available at https://github.com/zhangjuncsu/Diphase. Supplementary data are available at Bioinformatics online.

The role of Toll-like receptor 4 Asp299Gly genetic polymorphism in rehabilitation of patients with post-COVID syndrome

Introduction. The multivariability of the clinical course of post-covid syndrome (PCS) is associated with genetic heterogeneity of the population, which leads to a high interest in the study of genotypes. Aim. To evaluate the role of Toll-like receptor 4 (TLR4 (Asp229Gly) polymorphism in the formation of PCS and rehabilitation potential. Materials and methods. The study included 92 patients diagnosed with PCS between the ages of 21 and 75. All patients received a comprehensive clinical, laboratory, functional examination and quality of life assessment at admission and discharge. Deoxyribonucleic acid isolation and allele-specific polymerase chain reaction were performed from whole blood using «Lytech» kits (Russia) according to the manufacturer's instructions. Formation of groups for statistical processing was carried out in accordance with the results of genetic analysis. Patients received comprehensive rehabilitation, including: climatotherapy, exercise therapy, massage, aromatherapy, respiratory therapy. Performance was assessed based on the dynamics of the studied indicators. Results and discussion. Of the 92 patients included in the study, 22 (23.9 %) were AA homozygotes, 33 (35.8 %) were GG, and 37 (40.3 %) were AG heterozygotes. By age, the groups were comparable. The gender ratio was predominantly female in all groups. According to the initial characteristics, the condition of patients with more pronounced clinical symptoms was in the group of patients with the AG genotype. All groups showed varying degrees of positive dynamics. The dependence of the severity of PCS and the effectiveness of rehabilitation on genetic predisposition was established. Different severity of initial clinical symptoms and deviations of functional parameters were revealed. Significant differences were found when assessing the effectiveness of rehabilitation. Positive dynamics was observed in all groups, but most successfully in the AG group. This confirms the role of TLR4 in the immunological response to SARS-CoV-2 and its genetic polymorphism in a wide range of manifestations of both acute COVID-19 and PCS. Conclusions. The effectiveness of rehabilitation in patients with PCS is interrelated with the genetic heterogeneity of TLR4. The heterozygous variant of the AG genotype forms more pronounced clinical manifestations of PCS, but also a higher rehabilitation potential, which contributes to the successful completion of rehabilitation. The minor allele TLR4 (Asp299Gly) G is associated with a worsening of the course of PCS. Patients with the homozygous GG genotype need a longer course of rehabilitation.

Hypotonic syndrome as a manifestation of an ultra-rare disease caused by a new and de novo variant in the PLA2G6 gene

Introduction: congenital hypotonia, a rare condition that encompasses various neuromuscular disorders, can have a genetic origin, such as infantile neuroaxonal dystrophy (inad), an ultra-rare neurodegenerative disorder of unknown prevalence. Objective: to utilize genomic techniques for the precision diagnosis of low-prevalence neuromuscular diseases. Materials and methods: case report of an infant, without a family history of genetic diseases, normal pregnancy, hypotonia at birth, neurodevelopmental regression, nystagmus, strabismus, and cerebellar atrophy. Due to the suspicion of an autosomal recessive vs de novo inherited disease, genetic sequencing studies using ngs (next-generation sequencing) + cnv (copy number variations) were requested for genes related to congenital hypotonia (1,621 genes). Results: two heterozygous variants were identified (compound heterozygote for the pla2g6 gene), the first variant classified as probably pathogenic, a duplication of 5 nucleobases at position 1,914 of the cdna, in exon 14 of the gene. The second variant, classified as pathogenic, involves a change from guanine to adenine at position 2,081 of the cdna, in exon 15 of the gene. Variants in this gene are associated with three autosomal recessive medical conditions: infantile neuroaxonal dystrophy 1, neurodegeneration with brain iron accumulation 2b, and parkinsons disease 14. Discussion and conclusion: congenital hypotonia, linked to disorders such as inad, is difficult to diagnose conventionally. Deleterious variants in the pla2g6 gene, located on chromosome 22, are associated with three autosomal recessive hereditary conditions, including inad, with manifestations before 3 years of age, neurological symptoms, mortality within the first decade, and multiple complications. Genomic technologies, including reverse phenotyping, are fundamental in understanding its genetic basis, phenotypic heterogeneity, guiding targeted treatment, prognosis, follow-up, genetic counseling, and heritability risk, bringing us closer to anticipatory, preventive, and precision medicine, especially in ultra-rare conditions.

The possible association of two novel heterozygous GNB1 variants with obesity and metabolic disorders.

Variants in the GNB1 gene, which encodes for the beta-1 subunit of G proteins, have been associated with intellectual development disorder (OMIM: 616973), characterized by developmental delay, infantile hypotonia, seizures, and psychiatric problems. GNB1 variants may also cause a multisystem disorder, with symptoms such as hearing and vision impairment, gastrointestinal disorders, genitourinary abnormalities, and growth delay. We present two pediatric patients with two novel GNB1 variants. The first patient is a 12-year old Caucasian European female with a history of neonatal hypotonia, feeding difficulties, and failure to thrive for the first 2 years of life. Subsequently, she developed grade 3 obesity, hyperphagia, and autoimmune thyroiditis. Whole Exome Sequencing (WES) revealed a novel likely pathogenic variant in the GNB1 gene (NM_002074.5:c.93_94del, p.Gln32AspfsTer46), which is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. The second patient is a 2-year old Roma female with severe failure to thrive during infancy, congenital hypothyroidism, and transient hyperoxaluria. No developmental delay was identified. Genetic testing excluded primary hyperoxaluria and WES revealed to be a novel likely pathogenic variant {NM_002074.5:c.183G > T (NP_002065.1:p.Met61Ile), which is predicted to have a damaging effect on the gene or gene product. We present two rare pediatric cases with novel GNB1 variants which highlight the phenotypic variability associated with disrupted GNB1 expression. GNB1 may serve as a candidate gene for severe early onset obesity, hyperphagia, neurodevelopmental delay, and other metabolic and endocrine disorders.

De novo genetic variant in epileptic encephalopathy: Importance of specific diagnosis

Introduction: Early infantile epileptic encephalopathies (EIEE) are rare syndromes that affect neurological development. The etiology has been uncertain for a long time, but advances in genetics have identified numerous associated genes. Variants in the CYFIP2 gene have been linked to EIEE. Clinical case: An 11-year-old female born at term without complications, with microcephaly, synophrys, and short neck. No relevant family history. At one month, she developed generalized seizures and delayed neurodevelopment, progressing to severe spastic quadriparesis, requiring gastrostomy and tracheostomy, with paroxysmal discharges on electroencephalogram. She received multiple anticonvulsant medications and ketogenic therapy. Complete individual exome sequencing and analysis of deletions and duplications were requested. Individual complete exome + deletions and duplications analysis (CNV) identified a probably pathogenic heterozygous variant in the CYFIP2 gene variant c.259C>T (p.Arg87Cys) missense type, allelic ratio (VAF) 0.45. The results of this molecular study support the diagnosis of developmental and epileptic encephalopathy de novo. Discussion: Developmental and epileptic encephalopathy (EED) disorders are severe conditions that begin in childhood, characterized by epileptic seizures, abnormalities in the electroencephalogram, and deterioration of neurodevelopment. Genetic EEDs are associated with variants in various genes related to cellular and neuronal functions. The CYFIP2 gene, on chromosome 5q33.3, encodes protein 2 that interacts with FMRP (fragile X mental retardation protein), playing a crucial role in neurological development. De novo variants, such as nonsense mutations and truncation in CYFIP2, are associated with intellectual disability, seizures, and muscle hypotonia. Advancements in genomics are improving the understanding of epilepsy, impacting targeted treatment, prognosis, and patient counseling. Childhood epilepsy has a heterogeneous genetic basis, and some patients without previous diagnosis can now receive one, crucial for the implementation of precision medicine.

A Novel Heterozygous NFKB2 Variant in a Multiplex Family with Common Variable Immune Deficiency and Autoantibodies Against Type I IFNs.

We studied a family with three male individuals across two generations affected by common variable immune deficiency (CVID). We identified a novel missense heterozygous variant (c.2602T>A:p.Y868N) of NFKB2 in all patients and not in healthy relatives. Functional studies of the mutant allele in an overexpression system and of the patients' cells confirmed the deleteriousness of the NFKB2 variant and genotype, respectively, on the activation of the non-canonical NF-κB signaling pathway. Impaired processing of p100 into p52 underlies p100 accumulation, which results in gain-of-function (GOF) of IκBδ inhibitory activity and loss-of-function (LOF) of p52 transcriptional activity. The three patients' plasma contained autoantibodies that neutralized IFN-α2 and/or IFN-ω, accounting for the severe or recurrent viral diseases of the patients, including influenza pneumonia in one sibling, and severe COVID-19 and recurrent herpes labialis in another. Our results confirm that NFKB2 alleles that are IκBδ GOF and p52 LOF can underlie CVID and drive the production of autoantibodies neutralizing type I IFNs, thereby predisposing to severe viral diseases.

Novel biallelic GNE variants identified in a patient with chronic thrombocytopenia without any symptoms of myopathy.

GNE encodes a rate-limiting enzyme that regulates the biosynthesis of a sialic acid precursor. As sialic acids are critical for the platelet membrane and muscle fibers, GNE variants cause GNE-related thrombocytopenia and GNE-related myopathy. Here, we report a neonate with thrombocytopenia that initially met the criteria for neonatal allo-immune thrombocytopenia (NAIT) but was resistant to treatments and then revealed novel biallelic heterozygous GNE variants without any symptoms of myopathy when diagnosed. NAIT was initially diagnosed due to alloantibodies against HPA5 and its mismatch between the patient and his mother. However, intravenous immunoglobulin therapy and platelet transfusions showed minimal improvement in the platelet count. Platelet counts remained around 60 × 109/L, suggesting congenital thrombocytopenia. Gene panel sequencing at the age of 13 identified biallelic pathogenic variants of GNE. The patient did not exhibit any symptoms of muscular weakness, suggesting GNE-related myopathy. We demonstrated a GNE-related thrombocytopenia patient with novel biallelic heterozygous GNE variants. Clinical trials have involved the use of sialic acids or their precursors, as well as gene therapy, to treat GNE-related myopathy, which may slow or halt the progression of the disease. Therefore, early diagnosis of this disease may significantly impact its clinical course.

CFAP43 variant in persistent respiratory symptoms after hematopoietic cell transplantation

We describe a case of RAS-associated autoimmune leukoproliferative disease with primary ciliary dyskinesia (PCD)-like symptoms, such as recurrent pneumonia, sinusitis, and otitis media, that occurred 7 years after hematopoietic cell transplantation. Whole-exome sequencing revealed a heterozygous CFAP43 nonsense variant. Environmental factors related to hematopoietic cell transplantation may have led to PCD symptoms in this patient with this variant. Genetic screening can help avoid subsequent complications during patient management.

Intermittent episodes of acute severe encephalomyopathy and early death in two siblings caused by biallelic likely pathogenic variants in FASTKD2: Expanding phenotype and literature review.

Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine-threonine kinase domain 2 (FASTKD2) (MIM# 612322). COXPD44 is characterized by variable clinical features-developmental delay, chronic epileptic encephalopathy, seizure disorder/status epilepticus and cerebellar ataxia. We ascertained one sibwith episodic acute encephalomyopathy triggered by acute gastroenteritis and associated with haematological abnormalities, rhabdomyolysis leading to acute kidney injury, hypotensive shock leading to early death and a similarly affected sib with early death. Both siblings were normal neurologically in between the acute episodes. Whole exome sequencing (WES) was performed in the elder sibling. Mitochondrial respiratory chain enzyme activity assaywas performed in fibroblast cells and muscle tissue of the elder sibling. Also, Adenosine triphosphate (ATP) determination assay was done in fibroblast cells of the elder sibling. WES revealed compound heterozygous missense likely pathogenic variants in FASTKD2. Mitochondrial respiratory chain enzyme activity in muscle tissue showed reduced complex IV activity and ATP determination assay showed a reduction of ATP in skin fibroblasts. Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in FASTKD2 associated with the variable phenotypes and mitochondrial OXPHOS defect.

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy: QARS1 variants associated with a severe phenotype in a patient

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy is a rare disease due to QARS1 pathogenic variants altering the Glutaminyl-tRNA synthetase 1 activity. We report a Tunisian child presenting with neonatal onset seizures, severe psychomotor delay, retinal abnormalities and MRI cerebral supratentorial atrophy lesions. Whole exome and Sanger sequencing revealed two compound heterozygous variants of QARS1. Three-dimensional analysis of the mutant Glutaminyl-tRNA synthetase 1 predicted altered catalytic and tRNA-binding functions. Genotype–phenotype correlations emphasize the combined effect of the zygosity and the location of the pathogenic variants within the protein domains on the severity of the disease.

A parent and child with Liddle syndrome diagnosed correctly with the child as the proband: a case report with review of literature.

Liddle syndrome (LS) is an autosomal dominant genetic disorder characterized by early onset hypertension, hypokalemia, and low plasma aldosterone or renin concentration. It is caused by mutations in subunits of the epithelial sodium channel (ENaC). The clinical phenotypes of LS are variable and nonspecific, making it prone to both misdiagnosis and missed diagnosis. Genetic analysis is necessary to confirm the diagnosis of LS. Herein, we report the case of a 42-year-old male with LS and a 30-year history of hypertension. He was being treated for possible primary aldosteronism (PA) over the preceding 7 years; however, his hypertension was poorly controlled despite intensive combination therapy. His 13-year-old son served as a proband for a diagnosis of LS, as he had hypertension, hypokalemia, and a significant family history of hypertension. Genetic testing revealed a heterozygous pathological variant in the SCNN1B gene. This led to a diagnosis of LS, as the father was found to harbor the same mutation. Both were treated with ENaC inhibitors and a salt-restricted diet, which improved their symptoms markedly. The son's genetic diagnosis facilitated the subsequent proper diagnosis and treatment of his father. LS causes early onset hypertension; hence, its early diagnosis and treatment can prevent complications. Hereditary hypertension should be considered in cases of early onset hypertension with a significant family history. Patients diagnosed with PA using outdated criteria may have concomitant LS and require careful evaluation of biochemical and endocrine tests according to the current criteria.

ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis.

Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.

Whole-genome sequencing to identify rare variants in East Asian patients with dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common form of age-related dementia, following Alzheimer’s disease (AD). DLB is associated with a worse prognosis than AD and is characterized by a more rapid progression of cognitive impairment and a poorer quality of life. In addition, the pathogenesis of DLB is less understood than that of AD, and only three genes—SNCA (α‐synuclein), APOE (apolipoprotein E), and GBA1 (glucosylceramidase beta 1)—have been convincingly demonstrated to be associated with DLB. In this study, we utilized whole-genome sequencing data from 1744 Japanese individuals, comprising 45 DLB patients and 1699 cognitively normal older adults, aiming to identify new genes associated with DLB. Our genome-wide association studies of genes with potentially deleterious mutations identified the CDH23 gene as being associated with DLB, reaching a Bonferroni-corrected significance (P = 7.43 × 10−4). The gene contained three ethnicity-specific heterozygous missense variants (rs181275139, rs563688802, and rs137937502). CDH23 has been linked to deafness syndromes, and DLB patients carrying these mutations displayed symptoms of subjective hearing loss, suggesting a potential association between DLB onset and auditory impairment. Additionally, we explored human leukocyte antigen (HLA) genotypes associated with DLB but found no significant associations. This result suggests that the pathology of DLB differs from that of Parkinson’s disease, which has been reported to have an association with HLA. Although a limitation of this study is the lack of replication of our findings, which require further validation in independent cohorts, our study enhances the understanding of the etiology of DLB in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.

Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.

Juvenile parkinsonism is an exceedingly rare condition in which clinical signs of parkinsonism manifest before 21 years of age. Although the genetic underpinnings of this disorder are increasingly recognized, the full range of inherited metabolic contributors remains undefined. We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant. A 13-year-old patient presented with rapid progression of dysphagia, dysarthria, and loss of ambulation over 18 months. Whole-exome sequencing revealed compound heterozygous variants in the DPYS gene (NM_001385: c.1393C>T, p.R465X, and c.905G>A, p.R302Q). In silico analysis predicted both variants to be pathogenic. Further urinary metabolome analysis demonstrated markedly elevated dihydrouracil and dihydrothymine levels, confirming impaired pyrimidine metabolism. Levodopa treatment effectively relieved the patient's motor symptoms. This report identifies DPYS as a novel genetic cause of juvenile parkinsonism and underscores the potential efficacy of levodopa therapy in managing motor dysfunction in DYPS-related parkinsonism.

Clinical and genetic characteristics of children with Pitt-Hopkins syndrome caused by TCF4 gene variants

The clinical data of children with Pitt-Hopkins syndrome (PTHS) who were treated in the Affiliated Women and Children's Hospital of Ningbo University from September 2022 to January 2024 were retrospectively included. The patients were followed up to June 2024, and their clinical and genetic characteristics were analyzed. A total of 4 children were included, 2 males and 2 females, with a diagnostic age [M (Q1, Q3)] of 22 (10, 32) months. All the patients presented with typical facial and overall developmental delay (developmental, motor and language delay). The 4 patients were found to harbor de novo heterozygous variants of the TCF4 gene, including the c.990G>A(p.S330S), c.1417_1418delinsT (p.Pro473ArgfsTer15), c.1028C>G (p.S343*) and c.500-2delinsTC. After 15 months of follow-up, all 4 patients received early rehabilitation treatment, and their gross motor function improved to varying degrees, while 3 patients had no improvement in language function. TCF4 gene variation in 4 children had phenotypic heterogeneity, and the main clinical manifestations were developmental delay, language development disorder and special facial features. Among the gene variation types, there was 1 case each of synonym variation, frameshift variation, nonsense variation and splicing variation.

Unprecedented Co-occurrence: Identification of a Pathogenic Genetic Variant in the KMT2B Gene in a Wilson Disease Patient with a Pathogenic ATP7B Mutation

The pathophysiology of dystonia in Wilson disease (WD) is complex and poorly understood. Copper accumulation in the basal ganglia, disrupts dopaminergic pathways, contributing to dystonia’s development via neurotransmitter imbalance. Despite advances in diagnosis and management, WD with dystonia remains a challenging condition to treat. We aim to report the unprecedented co-occurrence of pathogenic genetic variants in both the ATP7B and KMT2B genes in a patient with WD. A 13-year-old male presented at 12 with dysarthria and bilateral Kayser-Fleischer rings. Over months, dystonia spread to his left foot, upper limb, and trunk, accompanied by slowed daily activities. Diagnostic tests included MRI for brain structure, abdominal ultrasound for liver function, serum ceruloplasmin and copper levels to assess copper metabolism, and 24-hour urine copper tests for excretion levels. Whole exome sequencing was conducted using genomic DNA from peripheral blood samples. Variant classification followed guidelines from the American College of Medical Genetics and Genomics. The sequencing revealed compound heterozygous pathogenic variants in the ATP7B gene: NM_000053.4:c.2165dupT and NM_000053.4:c.813C>A. A pathogenic variant in the KMT2B gene, NM_014727:c.3052delA, was identified. This case highlights WD co-occurrence with ATP7B and KMT2B mutations, suggesting KMT2B as a potential genetic modifier.

Portal hypertension in doublecortin domain‐containing protein 2 (DCDC2) related neonatal sclerosing cholangitis

AbstractMutations in doublecortin domain‐containing protein 2 (DCDC2) lead to neonatal sclerosing cholangitis (NSC), and portal hypertension (PHTN). The objective of the study was to systematically evaluate PHTN, variceal bleeding, and outcomes of patients with DCDC2‐related NSC. The study included children with homozygous or compound heterozygous variants in DCDC2. All 14 children with DCDC2‐related NSC had PHTN. Eight (57.1%) developed variceal bleed at a median age of 3 years (range: 1.9–5 years). Eleven (78.6%) children with high‐risk varices underwent endotherapy. Varices were completely eradicated in three, downstaged to low‐risk in five, and there was no response with endotherapy in three. All three children with failure to eradicate/downstage varices had rebleed, and required listing for liver transplantation (LT). The study shows that children with variants in DCDC2 have a high incidence of variceal bleed at a very young age. Variceal eradication may often be difficult and rebleed rates are high; often necessitating LT.

The Glu86 Residue in TBX4 Proves Critical for Human Lung Development.

T-box transcription factors are a group of evolutionarily conserved T-box-containing regulators of mesoderm specification and development. Heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving dosage-sensitive TBX4 have been associated with pulmonary arterial hypertension (PAH), ischiocoxopodopatellar syndrome with or without PAH, and lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary pulmonary hypoplasias. Loss- and gain-of-function variants have been proposed to cause pediatric PAH and LLDDs, and adult forms of PAH, respectively. Of more than 50 missense SNVs scattered across the entire TBX4, only three have been reported in patients with LLDDs, all mapping to the T-box domain. Here, we report a recurrence of a pathogenic substitution Glu86Lys identified in an unrelated patient with AcDys. In silico predictions of the conformational changes of TBX4 resulting from this and another substitution, Glu86Gln, suggest the loss of most intermolecular hydrogen bonds involving residue 86, including those with Tyr230 that directly interact with DNA. Functional assays on the TBX4 variants in fetal lung fibroblasts confirmed their deleterious character. We propose that Glu86 is critically involved in maintaining TBX4 structure and function essential for airway branching during early stages of human lung development. Substitutions of this residue may act in a dominant negative manner, leading to AcDys and CAD.