Chromosome 11q13 Research Articles

P-27 H SYNDROME: CASE REPORT

Abstract Introduction H Syndrome is an autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, and induration with numerous systemic manifestations. The syndrome is caused by mutations in SLC29A3, a gene located on chromosome 10q23, which encodes the human equilibrative transporter 3 (hENT3). H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect multiple organ systems. We are presenting first possible case of H syndrome reported in Iraq up to our knowledge. Clinical Case A 14 year old Iraqi boy presented with abnormal lower limb hyperpigmentation, and symmetrical, indurated plaques with marked hypertrichosis over medial aspect of thighs and legs. The skin hyperpigmentation was not itchy and did not involve the feet and knees. This hyperpigmentation had been present for several months. The patient was known to have type 1 diabetes mellitus (DM) since 5 years of age and was treated with insulin with fair control, although without features of advanced microvascular diabetic complications. The patient had deafness and he was wearing a hearing aid device recently. Laboratory analysis showed normal kidney and liver function and normal blood counts but with subclinical hypothyroidism and surprisingly positive serology for celiac disease and this feature was not reported in the few documented cases in the literature. Conclusion This rare syndrome of skin hyperpigmentation, diabetes and deafness may represent the first reported case of H syndrome in Iraq and occurrence of celiac disease is another manifestation that could be part of this syndrome.Figure 1:Hyperpigmentation

DICER1: The Argonaute Endonuclease Family Member and Its Role in Pediatric and Youth Pathology.

In 2001, two enzyme-encoding genes were recognized in the fruit fly Drosophila melanogaster. The genetic material, labeled Dicer-1 and Dicer-2, encodes ribonuclease-type enzymes with slightly diverse target substrates. The human orthologue is DICER1. It is a gene, which has been positioned on chromosome 14q32.13. It contains 27 exons, which are linking the two enzyme domains. DICER1 is found in all organ systems. It has been proved that it is paramount in human development. The protein determined by DICER1 is a ribonuclease (RNase). This RNase belongs to the RNase III superfamily, formally known as 'endoribonuclease'. It has been determined that the function of RNase III proteins is set to identify and degrade double-stranded molecules of RNA. DICER1 is a vital "housekeeping" gene. The multi-domain enzyme is key for small RNA processing. This enzyme functions in numerous pathways, including RNA interference paths, DNA damage renovation, and response to viruses. At the protein level, DICER is also involved in several human diseases, of which the pleuro-pulmonary blastoma is probably the most egregious entity. Numerous studies have determined the full range of DICER1 functions and the corresponding relationship to tumorigenic and non-neoplastic diseases. In fact, genetic mutations (somatic and germline) have been detected in DICER1 and are genetically associated with at least two clinical syndromes: DICER1 syndrome and GLOW syndrome. The ubiquity of this enzyme in the human body makes it an exquisite target for nanotechnology-supported therapies and repurposing drug approaches.

Lactylation modulation identifies key biomarkers and therapeutic targets in KMT2A-rearranged AML

Acute Myeloid Leukemia (AML) with KMT2A rearrangements (KMT2Ar), found on chromosome 11q23, is often called KMT2A-rearranged AML (KMT2Ar-AML). This variant is highly aggressive, characterized by rapid disease progression and poor outcomes. Growing knowledge of epigenetic changes, especially lactylation, has opened new avenues for investigation and management of this subtype. Lactylation plays a significant role in cancer, inflammation, and tissue regeneration, but the underlying mechanisms are not yet fully understood. This research examined the influence of lactylation on gene expression within KMT2Ar-AML, initially identifying twelve notable lactylation-dependent differentially expressed genes (DEGs). Using advanced machine learning techniques, six key lactylation-associated genes (PFN1, S100A6, CBR1, LDHB, LGALS1, PRDX1) were identified as essential for prognostic evaluation and linked to relevant disease pathways. The study also suggested PI3K inhibitors and Pevonedistat as possible therapeutic options to modulate immune cell infiltration. Our findings confirm the critical role of lactylation in KMT2Ar-AML and identify six key genes that may serve as biomarkers for diagnosis and treatment. In addition to highlighting the need for further validation in clinical settings, these findings contribute to our understanding of KMT2Ar-AML’s molecular mechanisms.

Cortex-specific Tmem169 Deficiency Induces Defects in Cortical Neuron Development and Autism-like Behaviors in Mice.

The development of the nervous system is a complex process, with many challenging scientific questions yet to be resolved. Disruptions in brain development are strongly associated with neurodevelopmental disorders, such as intellectual disability and autism. While the genetic basis of autism is well established, the precise pathological mechanisms remain unclear. Variations on chromosome 2q have been linked to autism, yet the specific genes responsible for the disorder have not been identified. This study investigates the role of the transmembrane protein 169 (Tmem169) gene, located on human chromosome 2q35, which has not been previously characterized. Our findings indicate that Tmem169 is highly expressed in the nervous system, and its deletion in the male mouse dorsal forebrain results in neuronal morphological abnormalities and synaptic dysfunction. Notably, Tmem169-deficient mice, irrespective of sex, display behavioral traits resembling those observed in individuals with autism. These results suggest that Tmem169 interacts with several key neuronal proteins, many of which are implicated in neurodevelopmental diseases. Furthermore, we demonstrate that Tmem169 promotes neuronal process and synapse development through its interaction with Shank3.Significance statement The prevalence of autism worldwide is estimated to be around 1-2%, causing significant burdens for both patients and their families. Our research reveals that Tmem169 not only interacts with important protein products of genes associated with autism, but also influences the levels of many critical synaptic proteins at synapses. We also demonstrated Tmem169 modulates neuronal process and synapse development at least partially via Shank3. Specific knockout of the Tmem169 gene in the cortex of mice induce autism-like behaviors. These findings provide the first insight into the role of the Tmem169 gene in neurodevelopment and offer new avenues for potential treatments and serve as an important theoretical basis for early screening and enhancing population quality related to autism.

Ancient viral DNA in the human genome linked to neurodegenerative diseases

BackgroundHuman endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision. MethodsWe analysed genetic association statistics pertaining to Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson’s disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses. ResultsThe primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61_12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE_1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules. ConclusionsWe found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention.

Screening Methods to Discover the FDA-Approved Cancer Drug Encorafenib as Optimally Selective for Metallothionein Gene Loss Ovarian Cancer.

All 11 metallothionein protein-coding genes are located on human chromosome 16q13. It is unique among human genetics to have an entire pathway's genes clustered in a short chromosomal region. Since solid tumors, particularly high-grade serous ovarian cancer (HGSC), exhibit high rates of monoallelic aneuploidy, this region is commonly lost. Studies have not yet been performed to determine what vulnerability may be created in cancer cells with low metallothionein expression. Here, a screen of FDA-approved cancer small molecule drugs for those best targeting low metallothionein ovarian cancer was completed. Screening methods were tested and compared using vehicle-treated negative controls and cadmium chloride, a positive control for cell loss selective for low metallothionein cells. CAOV3 cells, which are unique in their expression of only two metallothionein isoforms, were used, with or without shRNA knockdown of the predominantly expressed MT2A gene. A library of FDA-approved molecules was then screened. The optimal assay utilized Hoechst 33342 nuclear staining and mechanized fluorescent microscope counting of cell content. Encorafenib, an RAF inhibitor, was identified as the most selective for enhanced cytotoxicity in MT2A knockdown cells compared to scrambled controls. The nuclear stain Hoechst 33342, assessed by fluorescence microscopy, provides a low variance, moderate throughput platform for cancer cell loss screens. Low metallothionein ovarian cancer cells exhibit a vulnerability to the RAF inhibitor encorafenib.

Prenatal diagnosis and molecular cytogenetic analyses of a rare 17q12 microduplication family.

To report a rare 17q12 microduplication family. A 29-year-old woman (gravida 1, para 0) underwent amniocentesis at 21weeks' gestation because of double bubble sign and polyhydramnios of the fetus on prenatal ultrasound. Chromosomal microarray analysis (CMA) from this family revealed a 1.78-Mb microduplication on chromosome 17q12 of the fetal, spanning from position 34,460,444 to 36,243,365 (GRCh37). Trio whole-exome sequencing (WES) showed 17q12 microduplication in the fetal and the mother. After genetic counselling and being informed of the unfavourable prognosis, the parents decided to continue the pregnancy. We provide a detailed description of the phenotype in a rare family with 17q12 microduplication. Combination of karyotype analysis, CMA, WES, prenatal ultrasound and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

Metabolic profiling reveals altered amino acid and fatty acid metabolism in children with Williams Syndrome

Williams Syndrome (WS) is a rare neurodevelopmental disorder with a prevalence of 1 in 7500 to 1 in 20,000 individuals, caused by a microdeletion in chromosome 7q11.23. Despite its distinctive clinical features, the underlying metabolic alterations remain largely unexplored. This study employs targeted metabolomics to investigate the metabolic characteristics of children with WS. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified significant dysregulation of 15 metabolites, with 11 upregulated and 4 downregulated. Notably, amino acids such as alanine, proline, and arginine were significantly elevated. Fatty acid metabolism showed pronounced upregulation of long-chain saturated fatty acids (C18:0, C20:0, C22:0, C24:0, C26:0, and C28:0) and downregulation of long-chain unsaturated fatty acids (C18:2 LA, C22:6 DHA, C16:1 PLA, and t-C18:1 EA), except for upregulated nervonic acid (C24:1) and arachidonic acid (C20:4). Metabolic pathway analysis highlighted disruptions in arginine synthesis, arginine/proline metabolism, alanine, aspartate and glutamate metabolism, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and arachidonic acid metabolism. This study provides the first comprehensive analysis of amino acid and fatty acid metabolism in children with WS, offering insights into the disorder’s complex metabolic landscape. Further validation in larger cohorts is essential to confirm these findings and their potential as biomarkers and therapeutic targets.

The emerging role of long non-coding RNA SOX2-OT in cancers and non-malignant diseases.

SOX2 overlapping transcript (SOX2-OT) is a long non-coding RNA located at chromosome 3q26.33 in humans. Convincing data confirm that SOX2-OT is evolutionarily conserved and plays a significant role in various malignant and non-malignant diseases. In most cancers, the upregulation of SOX2-OT acts as an oncogenic factor, strongly correlating with tumor risk, adverse clinicopathological features, and poor prognosis. Mechanistically, SOX2-OT is regulated by seven transcription factors and influences cellular behavior by modulating SOX2 expression, competitively binding 20 types of miRNAs, stabilizing protein expression, or promoting protein ubiquitination. It also participates in epigenetic modifications and activates multiple signaling pathways to regulate cancer cell proliferation, apoptosis, migration, invasion, autophagy, immune evasion, and resistance to chemotherapy/targeted therapies. Additionally, SOX2-OT triggers apoptosis, oxidative stress, and inflammatory responses, contributing to neurodevelopmental disorders, cardiovascular diseases, and diabetes-related conditions. Genetic polymorphisms of SOX2-OT have also been linked to breast cancer, gastric cancer, recurrent miscarriage, sepsis, and eating disorders in patients with bipolar disorder. This review provides an overview of recent research progress on SOX2-OT in human diseases, highlights its substantial potential as a prognostic and diagnostic biomarker, and explores its future clinical applications.

Neurofibromatosis type 1 and High-risk Pregnancy: A Case Report

Introduction: A high-risk pregnancy is the result of a disease present before pregnancy. Neurofibromatosis type 1 is a rare disease during pregnancy, autosomal dominant, with a mutation in the NF1 gene, on chromosome 17q11.2. Clinical case: 38-year-old woman, Gestational age 1. Mother with neurofibromatosis type 1. The patient is hypertensive, diagnosed 7 years ago and currently treated with alpha-methyldopa 250 mg every 12 hours orally. She reports the diagnosis of neurofibromatosis type 1 since childhood. Without adequate prenatal control, with alterations in the Doppler ultrasound and complication of intrauterine growth restriction stage 1. A referral is made to third level of care and evaluation by maternal-fetal medicine Discussion: Pregnancies in patients with neurofibromatosis are predisposed to obstetric complications due to the multisystemic nature of the disease. These patients have a higher incidence of spontaneous abortions, stillbirth, preeclampsia, intrauterine growth restriction (IUGR), oligohydramnios, premature birth and cerebrovascular complications.

A Novel Homozygous Synonymous Variant in CCDC134 as a Cause of Osteogenesis Imperfecta Type XXII.

Osteogenesis imperfecta (OI) is a heterogeneous group of rare, inherited connective tissue disorders. It includes over 20 defined subtypes, each of which is associated with distinct causative genes that are listed in the Online Mendelian Inheritance in Man (OMIM) database. Type XXII OI (OI 22) is caused by a homozygous variant in the coiled-coil domain containing 134 (CCDC134) gene, which is located on chromosome 22q13. OI, which is associated with CCDC134, is extremely rare with only five cases reported worldwide. All known cases involve the c.2 T > C (p. Met1Thr) homozygous missense variant in the CCDC134 gene. We present the case of a 13-year-old Chinese girl with non-union fracture, short stature and specific radiographic findings, which include scoliosis, pelvic tilt, thin clavicles, ribs, and limbs. Whole exome sequencing revealed a novel, homozygous c.492G > C (p. Leu164=) variation in the CCDC134 gene. RNA sequencing (RNA-seq) analysis identified this variant as an abnormal splicing variant that causes the deletion of Exon 5, which result in the observed disease phenotype. This case demonstrates the clinical phenotype of OI 22 associated with the c.492G > C (p. Leu164=) novel synonymous variation in the coding region of the CCDC134 gene in a female patient. This is the first reported case of OI 22 in the Chinese population, the sixth reported worldwide and the fourth reported genotype for diseases associated with a CCDC134 variant. It also enriches the global clinical phenotype spectrum of OI 22 patients.

Darya's disease: rare dermatosis with complicated manifestations

The pathogenesis of the disease is associated with mutations in the ATP2A2 gene of chromosome 12q23-24, which disrupt intracellular calcium metabolism. COVID-19 infection is known to cause a cytokine storm characterized by increased levels of tumor necrosis factor (TNF), interleukin (IL) 6 and 1β. TNF and IL-6 additionally reduce the activity of type 2 calcium ATPase in patients with Darye's disease. The typical clinical picture of rare hereditary dermatosis is characterized by hyperkeratotic papules located in seborrheic zones. Papules tend to fuse to form plaques. The surfaces of the palms and soles are also a frequent localization of the pathological process. Papules may grow into hypertrophic vegetations, damage to nails and oral mucosa, and the addition of secondary bacterial and viral infections. The typical course is of a continuous progressive nature with periods of exacerbation and incomplete remission. Systemic retinoids are the basis of therapy for Darye's disease. In addition, glucocorticosteroids and cyclosporine are systematically used. Local therapy includes keratolytic and antiseptic drugs, emollients. A case of clinical observation of a 39-year-old patient with Darye's disease is presented. The diagnosis was made based on the analysis of complaints, anamnesis, objective and local status, dermatoscopic picture, laboratory and histological examination. Against the background of ongoing therapy, the patient was discharged with clinical improvement and continues treatment on an outpatient basis. The clinical observation of this case is of interest to practicing dermatovenerologists.

De Novo Balanced Translocations Disrupting the FBN1 Gene Diagnosed by Genome Sequencing: An Uncommon Cause of Marfan Syndrome Modifying Genetic Counseling.

Marfan syndrome (MFS) is a well-characterized rare genetic connective tissue disorder. The features of MFS are primarily skeletal, ocular, and cardiovascular and are mainly caused by single-nucleotide variants (SNVs) in the FBN1 gene (MIM#134797) located on chromosome 15q21.1. We describe two patients, a 26-year-old male and a 10-year-old female from unrelated distinct families, with clinically diagnosed sporadic MFS. After years of unsuccessful molecular diagnosis for genetic counseling purposes, genome sequencing was performed and revealed a balanced translocation in both patients: de novo t(9;15)(p13.3;q21.1) translocation in the male patient, and de novo t(15;16)(q21.1;p13.13) translocation in the female patient, respectively, disrupting intron 40 and 45 of FBN1. The other breakpoints were not clinically relevant. These translocations were confirmed by specific fluorescence insitu hybridization probes and conventional karyotyping. In the literature, only one family has been described, leading to four cases of MFS caused by balanced translocations. Genetic counseling for balanced translocations differs from SNVs and even interstitial deletions since it is not restricted to MFS recurrence, but also involves the risk of unbalanced gametes, leading to miscarriage or unbalanced progeny. In case of clinical certainty, MFS patients should be screened for balanced translocations to ensure appropriate genetic counseling.

The Role of Synaptic Cargo Transporters in Regulating Neuronal Excitation/Inhibition Balance in Autism Spectrum Disorders: A Focus on Syntabulin-syntaxin 1 A/B Axis

Various cargo vesicles containing presynaptic proteins are transported from the neuronal cell body to the neuronal terminal to aid in active zone formation. Researchers showed altered levels up to 25 different synaptic proteins (SNAP47, GRIA3/4, GAP43, synaptotagmin 2, LRFN2, SV2C) and syntabulin. Syntabulin is a key component gene of a kinesin motor-adaptor complex essential for the forward movement of active zone components in axons. It plays a crucial role in the assembly of presynaptic structures during neuronal development in response to activity. However, the specific membranous cargoes and motor-cargo interactions are not fully understood. Recent research identified a syntaxin-1-binding protein called syntabulin. Syntabulin links syntaxin-containing vesicles to microtubules and moves with syntaxin in neuronal brain processes. Knocking down syntabulin expression or disrupting the syntabulin-syntaxin interaction hinders the attachment of syntaxin-cargo vesicles to microtubules and reduces syntaxin-1 distribution in neuronal processes. Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. Syntabulin could act as a linker molecule that connects syntaxin-cargo vesicles to kinesin I, facilitating the transport of syntaxin-1 to neuronal processes. Syntabulin also regulates neuronal excitatory and inhibitory imbalance by transporting syntaxin 1 B, more than syntaxin 1A, to the presynaptic membrane. The gene for Syntabulin is found on human chromosome 8q23.2, in mouse on chromosome 15. This review shed light on the role of syntabulin-syntaxin 1A/B axis and mention different synaptic cargo transporters which could play any role in autism spectrum disorders. Further research should focus to study synaptopathies in autism spectrum disorders to open new arenas for pharmaceutical interventions.

2q33 Deletions Underlying Syndromic and Non-syndromic CTLA4 Deficiency.

CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4. We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4. We investigated the clinical and immunological phenotypes and genotypes of these patients. We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single-nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes.We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype. Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

Nijmegen breakage Syndrome - how much do we know about this rare condition of Slavs? - disease overview

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive defect of immunity, characterised by chromosomal instability and radiation sensitivity with a high predisposition to malignancy. The clinical manifestations of this condition include microcephaly, combined immunodeficiency, growth retardation and a range of additional abnormalities, including facial, skeletal and skin anomalies (such as café au lait spots and vitiligo). It is estimated that 40% of patients will develop cancer before reaching the age of 21 years. [1-2] The aetiology of this syndrome can be attributed to a mutation in the NBS1 gene, which is localised on chromosome 8q21 and is responsible for the production of the protein nibrin. [3] The most common mutation responsible for NBS (c.657_661del5) is consistent with a founder effect, with the majority of registered patients originating from Central and Eastern Europe and the largest cohort diagnosed in Poland. [4] This article provides an overview of Nijmegen breakage syndrome (NBS), including epidemiology, symptoms, diagnostic pathway and patient management, as well as treatment options. The objective of this study is to enhance awareness of this condition in order facilitate an early diagnosis and screening for malignancy in patients.

A new cancer/testis long noncoding RNA, the OTP-AS1 RNA

The orthopedia homeobox (OTP) gene encodes a homeodomain-containing transcription factor involved in brain development. OTP is mapped to human chromosome 5q14.1. Earlier we described transcription in the second intron of this gene in wide variety of tumors, but among normal tissues only in testis. In GeneBank these transcripts are represented by several 300–400 nucleotide long AI267901-like ESTs. We assumed that the AI267901-like ESTs belonged to the longer transcript(s). We used the Rapid Amplification of cDNA Ends (RACE) approach and other methods to find the full-length transcript. The transcript we found was a 2436 nucleotide polyadenylated sequence in antisense to OTP gene. The corresponding gene consisted of two exons separated by an intron of 2961 bp. The first exon was found to be 91 bp long and located in the third exon of OTP. The second exon was 2345 bp long and located in the second intron of OTP. We have shown the expression of this gene in many human tumors but as few as a single sample of normal testis. The transcript lacked significant ORFs suggesting that we discovered a new antisense cancer/testis (CT) sequence OTP-AS1 (OTP—antisense RNA 1), which belongs to the class of long noncoding RNAs (lncRNAs). According to our findings we assume that OTP-AS1 and OTP genes may be a CT-coding gene/CT-ncRNA pair, or sense-antisense gene pair involved in regulatory interactions.

Exploring 17q12 Deletion Syndrome: A Case Report of Neurodevelopmental, Endocrine, and Genital Anomalies

Objective − 17q12 deletion syndrome is a rare genetic disease characterized by neurodevelopmental disorders, genital and renal abnormalities, and maturity-onset diabetes of the young type 5 (MODY5).Case Report − This case report details the case of a 13-year-old female with moderate intellectual disability, Mayer-Rokitansky-Küster-Hauser syndrome, multicystic dysplastic kidneys, and MODY5. Genetic testing revealed a 1.52-megabase heterozygous deletion on chromosome 17q12, encompassing the HNF1B and LHX1 genes, which was found to be inherited from the mother. Conclusion − This case underscores the importance of early genetic testing and multidisciplinary approach in managing the multisystemic manifestations of 17q12 deletion syndrome. Early diagnosis and appropriate management are crucial for improving the outcomes and quality of life for affected individuals.

Hearing impairment and vestibular function in patients with a pathogenic splice variant in the LHX3 gene

BackgroundLHX3 is a gene encoding a LIM-homeodomain transcription factor important for the fetal development of several organs, such as the pituitary gland, spinal motor neurons and the inner ear. Pathogenic and likely pathogenic variants in the LHX3 gene are infrequent and result in a rare syndrome known as combined pituitary hormone deficiency-3, CPHD3.MethodsWe have studied hearing and vestibular functions in a group of eight individuals, aged 8–36 years, all of whom were homozygous for a specific variant in the LHX3 gene at chromosome 9q34. We reexamined the results of consecutive hearing tests from newborn until April 2024. ResultsOur data showed that all the tested patients had progressive sensorineural hearing deficiency ranging from moderately severe to complete loss. We have performed vestibular testing in six patients and, for the first time, demonstrated that a mutation in the LHX3 gene not only affects hearing, but is also associated with vestibular impairment.ConclusionThe human pathogenic variant c.455-2A > G in the LHX3 gene on chromosome 9q34, which present as a founder mutation in the population in northern Sweden, is responsible for phenotypes associated with progressive hearing loss and balance impairment. These findings prove that the LHX3 gene is crucial for the function of both the cochlear and vestibular organs.

Four heterozygous de novo variants in ASXL3 identified with Bainbridge-Ropers syndrome and further dissecting published genotype-phenotype spectrum.

Bainbridge-Ropers syndrome (BRPS) is a recently described neurodevelopmental genetic disorder associated with de novo truncating variants in additional sex combs like 3 (ASXL3) on chromosome 18q12.1. Trio-based exome sequencing was conducted on patients admitted to the Children's Hospital Affiliated to Shandong University and diagnosed with unexplained intellectual disabilities or developmental delay between June 2022 and January 2024. De novo truncation of ASXL3 was identified in four patients, and the pathogenic variants and their de novo status were validated using Sanger sequencing. Comprehensive clinical phenotype-genotype information of all previously reported patients with BRPS was collected and summarized. The common clinical manifestations observed in the four patients included language and intellectual disabilities or psychomotor retardation. Genetic analysis revealed that patient 1 carried a de novo heterozygous variant, c.1667_1668del (p.Thr556Arpfs*3), whereas patient 2 had a novel heterozygous frameshift variant of ASXL3, c.3324del (p.Lys1109Serfs*34). These two variants have not been documented to date. Additionally, patients 3 and 4 exhibited a de novo variant, c.4678C > T (p.Arg1560Ter). Based on the combined assessment of clinical phenotypes and genetic testing results, it was postulated that all four children presented with BRPS syndrome caused by pathogenic variations in ASXL3. The present study complements the range of ASXL3 mutational and phenotypic spectra in the population, highlighting subtle distinctions in clinical manifestations between Chinese patients and other racial groups. The reporting of additional cases will contribute to further elucidating the function of ASXL3 and establishing a solid foundation for clinical diagnosis and treatment.