Autosomal Dominant Inheritance Research Articles

Research progress on GSDME-mediated cell pyroptosis resulting in GSDME type hearing loss

Pyroptosis is a novel mode for programmed cell death discovered and confirmed in recent years. The Gasdermins (GSDMs) family is a key effector molecule mediating pyroptosis. As an important cause of extensive inflammatory damage and side effects of conventional chemotherapy drugs, anomalous pyroptosis has also been associated with hearing loss, tumor, and disorders of the immune system. The GSDME protein, encoded by the GSDME (DFNA5) gene, belongs to the GSDMs family and is a key factor mediating pyroptosis. Gain-of-function variants of the GSDME gene can lead to GSDME-related hearing loss, which shows an autosomal dominant inheritance. This article has reviewed the role of GSDME-mediated pyroptosis in the pathogenesis of GSDME-related hearing loss, with an aim to provide insights into the treatment of GSDME-related hearing loss.

Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy

Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype–phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient’s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype–phenotype correlations.

C9orf72 Gene-Associated Frontotemporal Dementia Mimicking Autoimmune Pathology.

The C9orf72 mutation can manifest in diverse clinical ways, including rapid cognitive decline, parkinsonism, or late-life neuropsychiatric symptoms, sometimes mimicking autoimmune encephalitis. A 64-year-old female presented to the autoimmune neurology clinic with rapidly progressive dementia (RPD) associated with episodes of headache, confusion, auditory hallucinations, and abnormal electroencephalogram. She was treated empirically at an outside hospital for possible autoimmune encephalitis with intravenous methylprednisolone, but there was no improvement, and rapid cognitive decline continued. Family history was notable for RPD with akinetic mutism in her sister, sudden severe depression followed by parkinsonism with progressive dementia in her father in his 60s, and late-life gradually progressive dementia in her mother. Additional testing revealed a low titer positive contactin-associated protein-like 2 (CASPR2) immunoglobulin G (IgG) in the serum and elevated CSF 14-3-3 protein. CSF CASPR2 IgG and real-time quaking-induced conversion for Creutzfeldt-Jakob disease were negative. Brain MRI showed normal parenchymal volume. Genetic testing was conducted, which identified a heterozygous pathogenic hexanucleotide tandem repeat expansion in the C9orf72 gene. This case underscores the phenotypic variability of C9orf72 mutation and the importance of a detailed family history exploring young or atypical deaths and neuropsychiatric symptoms or behavioral changes. Genetic etiologies are crucial to consider in those with a family history concerning autosomal dominant inheritance patterns of early-onset dementia, parkinsonism, or late-onset psychiatric disease. Emphasis is placed on considering alternative etiologies early, particularly when there is no response to first-line immunomodulation for suspected autoimmune dementia.

Novel treatment options in patients with maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes that are important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While GCK-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY such as HNF1A-MODY (formerly MODY-3) and HNF4A (formerly MODY-1) usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports.

A novel variant in the 3′ UTR of the TCF4 gene likely causes Pitt-Hopkins syndrome: a case report

BackgroundPitt–Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder that results from variants of TCF4 gene. PTHS follows an autosomal dominant inheritance pattern and the underlying pathological mechanisms of this disease are still unclear.MethodsWhole-genome sequencing (WGS) was conducted to screen for potential pathogenic variant in a boy highly suspected of having a genetic disorder. PCR and Sanger sequencing were used to verify the effects of the variant. Serum TCF4 levels were measured by ELISA.ResultsWe present a 4-year and 3-month-old Chinese boy clinically and molecularly diagnosed with PTHS. The proband experienced global development delay, and the preliminary clinical diagnosis was cerebral palsy. WGS identified a de novo heterozygous variant: c.*1A > G in the 3’UTR of the TCF4 gene as a potential cause of his condition. The variant was verified to cause aberrant mRNA splicing by PCR and the aberrant splicing was confirmed by Sanger sequencing.ConclusionThe study identified and demonstrated the pathogenicity of a novel 3’UTR site TCF4 variant for the first time. This research enhances understanding of pathogenetic mechanisms of PTHS and aids genetic counseling and diagnosis.

7316 A Unique Presentation of Diabetes Mellitus in an 8-Year-Old Male Positive For 3 Different Mutations Related to MODY

Abstract Disclosure: R. Senguttuvan: None. A. Pamfil: None. Background: Maturity-Onset Diabetes of the Young (MODY) is the most common form of inherited non-autoimmune diabetes mellitus, characterized by autosomal dominant inheritance, young age at onset and beta cell dysfunction. There are at least 14 MODY mutations and we present a pediatric case not meeting criteria for type 1[T1DM] or type 2 diabetes mellitus[T2DM], who tested positive for mutations in 3 different genes known to cause MODY. Case: An 8-year-old male, born full term, 2776 grams and 48.3 cm, without history of neonatal hypoglycemia or hyperglycemia, was referred for new onset diabetes mellitus management. While undergoing evaluation for abdominal pain and constipation, he was found to have a fasting glucose of 126 mg/dL (7 mmol/L) and hemoglobin A1C of 6.5%. He endorsed polyuria, but no polydipsia. He had no clinical signs of insulin resistance (e.g., acanthosis nigricans) and a BMI of 23.65 kg/m2, at the 97th percentile. Family history is positive for diabetes mellitus requiring insulin, in father (diagnosed at 11 years) and paternal grandmother and T2DM in paternal aunt. Laboratory evaluation was negative for all 5 antibodies (GAD, IA-2, Anti-islet cell antibody, Zinc Transporter 8 and Insulin antibodies) and revealed an insulin level of 15.9 uIU/mL (RR: <2.0-13.0) and C peptide: 2.3 ng/mL (RR: 1.1-4.4). Lacking diagnostic criteria for T1DM or T2DM, genetic testing was performed. Patient tested heterozygous for mutations in 3 genes known to cause MODY: GCK [(c.350 G>T p. (G117V)], ABCC8 [(c.2270 C>G p.(T757R)], and HNF1B [(c.68A>G p.(K23R)], all variant of uncertain significance. Over an 8-month period, patient's weight decreased from 98 lbs. (44.9 kg) to 90 lbs. (41.1 kg) after meeting with our dietician and implementing healthy dietary changes, and his beta cell function markers improved from diagnosis: Fasting insulin (4.5 uIU/mL), C peptide (1.3 ng/mL), and glucose 119 mg/dL; Hemoglobin A1C remained relatively stable at 6.1%. A kidney ultrasound was normal. No medical intervention were started yet, and patient is being monitored clinically and biochemically every 3-4 months. Discussion: Clinical monitoring over time, genetic testing in the parents, are critical in this patient’s long-term treatment plan and prognosis. To our knowledge, this may be the first case of diabetes mellitus in a pediatric patient, positive for mutations in 3 different genes known to cause MODY. South Texas has one of the highest incidences of T2DM in the USA. In addition to screening for genetic forms of diabetes, in patients with negative T1DM antibodies and atypical phenotype for T2DM, we should consider genetic screening in mildly obese pediatric and young adult patients without significant acanthosis nigricans, who were already diagnosed as T2DM. Presentation: 6/1/2024

7328 A case of Adrenal Calcifications in a Patient with Familial Cerebral Cavernous Malformations

Abstract Disclosure: R.I. Dorin: None. L.E. Aguirre: None. M. Bomgardner: None. Background: Familial syndromes of cerebral cavernous malformation (fCCM) having autosomal dominant inheritance and variable penetrance and expression have been linked to loss of function mutations at three genetic loci. The association of small focal adrenal calcifications with fCCM was only recently recognized in a New Mexican cohort of subjects predominately carrying the founder common Hispanic mutation in the CCM1 locus (stop codon Q455X in the Krev1 interaction trapped gene 1 [KRIT1]). We report a case of bilateral, focal adrenal calcifications in a patient affected by fCCM. Clinical Case: A 72-year-old Hispanic male with past medical history of intracranial CCM was referred for osteoporosis and hyperthyroidism due to multinodular goiter. Small focal calcifications of the adrenal glands were incidentally noted on prior imaging studies. There was no history of anticoagulant use, adrenal hemorrhage, or systemic/adrenal infection. The patient was without clinical manifestations of adrenal insufficiency, morning cortisol and plasma ACTH concentrations were normal, and exam was negative for hyperpigmentation or cutaneous vascular malformations. Brain MRI revealed the presence of over 100 parenchymal CCM lesions. A family history of CCM was reported in multiple family members, including 7/10 siblings. Conclusion: In addition to cutaneous malformations, small focal adrenal calcifications are now recognized as one of the extra-neurological manifestations of fCCM, particularly in patients harboring the common Hispanic CCM1/KRIT1 mutation. Whether adrenal calcifications are observed in fCCM patients having other mutations of KRIT1 or other genetic loci of fCCM (CCM2 or PDCD10) remains to be determined. The focal adrenal calcifications are believed to be result of dyssynchronous, subclinical hemorrhagic events related to vascular malformations in the adrenal gland. These findings implicate a role for KRIT1 in endothelial development in the adrenal gland in addition to established role in CNS, spinal cord, and skin. Our patient appeared had normal adrenocortical function, as expected for the focal nature of the adrenal lesions. Though adrenal function has not been evaluated in fCCM patients, there are no reports of primary adrenal insufficiency in fCCM in the literature. Adrenal calcifications may be considered to represent an imaging biomarker for fCCM, and fCCM should be included in the differential diagnosis of adrenal calcifications. The incidental recognition of characteristic small, focal adrenal calcifications in either bilateral or unilateral adrenal glands should prompt evaluation for fCCM.

The membrane curvature-inducing REEP1-4 proteins generate an ER-derived vesicular compartment.

The endoplasmic reticulum (ER) is shaped by abundant membrane curvature-generating proteins that include the REEP family member REEP5. The REEP1 subfamily, consisting of four proteins in mammals (REEP1-4), is less abundant and lack a N-terminal region. Mutations in REEP1 and REEP2 cause Hereditary Spastic Paraplegia, but the function of these four REEP proteins remains enigmatic. Here we show that REEP1-4 reside in a unique vesicular compartment and identify features that determine their localization. Mutations in REEP1-4 that compromise curvature generation, including those causing disease, relocalize the proteins to the bulk ER. These mutants interact with wild-type proteins to retain them in the ER, consistent with their autosomal-dominant disease inheritance. REEP1 vesicles contain the membrane fusogen atlastin-1, but not general ER proteins. We propose that REEP1-4 generate these vesicles themselves by budding from the ER, and that they cycle back to the ER by atlastin-mediated fusion. The vesicles may serve to regulate ER tubule dynamics.

7850 Developmental ZNHIT3 expression in mice embryos in Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome related organs

Abstract Disclosure: D. Kira: None. B. Eroglu, MS, PhD: None. Z. Hawkins: None. L.P. Chorich: None. S. Brakta: None. L.C. Layman: None. Introduction: MRKH is a severe form of the Mullerian duct (MD) anomaly where the upper 2/3 of the vagina and the uterus fail to develop. Individuals with MRKH still have normally functioning ovaries and normal chromosomes. MRKH may be isolated Mullerian aplasia (type 1) or associated with renal, skeletal, cardiac, and/or auditory dysfunction (type 2). The etiology of MRKH syndrome remains unknown for most probands, although a genetic contribution is likely. Most evidence suggests autosomal dominant inheritance with incomplete penetrance. WNT4 and HNF1B pathogenic variants have been identified in some MRKH individuals. Recently, our lab identified heterozygous (HTZ) ZNHIT3 loss of function variants in persons with MRKH, Both variants predict functional changes in the ZNHIT3 C-terminus and impair protein expression in vitro. Previously, other investigators found biallelic variants in the N-terminus of ZNHIT3 in individuals with PEHO syndrome, a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy. We are currently characterizing a novel Znhit3 knockout (KO) mouse model, in which homozygous KO mice exhibit embryonic lethality. We have demonstrated ZNHIT3 RNA expression in the human uterus, heart, kidney, and skeleton, but developmental expression of ZNHIT3 in wild type (WT) animals has not been studied. In the WT mouse embryo, the kidney forms between E8.0 and E11, while the MDs form through invagination of epithelium ∼E11.5 and extend along the Wolffian duct until reaching the cloaca at ∼E13.5. Hypothesis: We hypothesize that ZNHIT3 is involved in MD development and expressed in the urogenital system and MRKH-related organs during embryonic development of WT mice. Method: Timed mating of WT mice produced embryos for analysis. Embryos were dissected out at E11.5, 12.5 and 13.5, fixed in 4% PFA, embedded in paraffin, and sectioned sagittally at 5mm thickness. H&E staining was done to identify sections showing kidney, genital tubercle, skeleton and cerebellum. Immunohistochemistry was also done using a ZNHIT3 antirabbit antibody and DAPI as nuclear counter stain. Imaging was performed using the Keyence fluorescence microscope (BZ-X800) at 10x and 40x magnification. Results: At all 3 time points, ZNHIT3 protein expression was observed in the developing urogenital organs including kidneys and bipotential gonads, as well as in vertebral bones and cerebellum. Heart protein expression studies are ongoing. Conclusion: ZNHIT3 protein expression is seen as early as E11.5 and is present in MRKH-related organs, suggesting it may play a role in the development of urogenital and MRKH-related organs. These findings provide the basis to compare expression in the Znhit3 KO mouse, a mouse model for MRKH. Presentation: 6/2/2024

Psychosocial impact on individuals who received negative test results from predictive testing for Huntington's disease: Anexploratory qualitative study.

Huntington's disease (HD) is a neurodegenerative disease with autosomal dominant inheritance, and no radical cure for HD has been established. Qualitative studies are necessary to investigate the psychological state of individuals who underwent predictive testing for HD, because the psychosocial impact on noncarriers remains unclarified in Japan. Herein, we elucidated the psychosocial impact on the noncarriers for HD and the role of genetic counseling for predictive testing and follow-up after testing by examining their experiences with predictive testing. We conducted semi-structured interviews with eight individuals participating in this study. Interview data were transcribed verbatim and evaluated according to thematic analysis. As a result, 4 themes were generated from 21 categories of 46 codes: (1) Diversity of perceptions concerning the test results, (2) Views on life as a noncarrier, (3) Changes in feelings toward and relationships with family members, and (4) Sharing information within the family. After receiving the negative results, the noncarriers felt not only relief but also surprise, doubt, relief from tension, and regret. It was shown that noncarriers felt survivor's guilt toward many unspecified individuals, which was not only a sense of guilt but also a sense of mission or responsibility. Additionally, they conducted altruistic behavior as members of their family and society, that may be related to the Japanese collectivism. Some participants were concerned about sharing information with their siblings. Noncarriers for HD can experience complex psychological states, and Japanese people who prefer high-context communication may find it difficult to express their feelings and thoughts. It is important to understand their true feelings before and after the predictive genetic testing, reconsider the impact of being a noncarrier and whether it is a burden for them from both subjective and objective perspectives, and conduct long-term follow-up as needed.

Case report: A novel de novo variant of NACC1 caused epileptic encephalopathy and intellectual disability

BackgroundGenetic disorders could also contribute to intellectual disability. Using whole exome sequencing (WES), several variants have been identified as autosomal-dominant inheritance intellectual disability. Thus, the application of WES has demonstrated its critical role in distinguishing intellectual disability in children patients, which provides essential diagnosis and promotes therapeutic strategy.Case presentationThe proband, an 18-month-old female patient, presented with a complex clinical profile characterized by profound developmental delay, epilepsy, and neurological developmental impairment. WES identified a heterozygous c.913A>G variant in exon 2 of NACC1, resulting in disease caused by a change in the amino acid sequence, affecting the protein features and resulting in splice site changes, as revealed by MutationTaster analysis. The protein structure of NAC1 was built and named AF-Q96RE7-F1, and the mutant site was beyond the BTB/POZ, NLS, and BEN domains. Subsequently, PyMOL software was used to illustrate the molecular structure between the wild type and the mutant type of NAC1. The residues around the 304 site of amino acid changed in NAC1 p.T304A with an altered hydrogen bond, indicating an unstable structure. The patient was diagnosed with intellectual disability and profound developmental delay with epilepsy harboring a novel de novo NACC1 variant. Upon hospital admission, a comprehensive treatment regimen was initiated, including antiseizure medications, nutritional supplements, and rehabilitation training. As a result, the patient’s movement performance improved. However, recurrent epilepsy attacks still occurred.ConclusionThis is the first case revealing a novel NACC1 c.903A>G variant that induced a neurological impairment in an infant. This report expanded the understanding of the non-domain-associated variant of NACC1 and developmental disorder.

Evaluation of the clinical features of an outpatient cohort with Marfan syndrome

Marfan syndrome is a connective tissue disease with autosomal dominant inheritance and variable clinical presentation. The main clinical manifestations recognition could contribute to early diagnosis and cardiovascular complication prevention. We aimed to evaluate the clinical profile of a Marfan syndrome outpatient cohort. MethodsRetrospective cross-sectional study was carried out with outpatients over 12 years of age whose electronic medical records contained the clinical information and complementary exams necessary for study inclusion. Data were analyzed using descriptive statistics and comparisons were performed using student's t-test and chi-square or Fisher's exact test. P-values<0.05 were considered statistically significant. Results75 patients (29.5 ± 13.4 years) were included and 43(57 %) were female. Positive family history for the syndrome was observed in 55(73 %) patients and ectopia lentis in 37(49 %). Positive systemic score (≥7) was identified in 60(80 %) individuals and the most frequent score components were: skin striae in 64(85 %), scoliosis in 59(79 %), wrist and thumb sign in 45(60 %), moderate or severe myopia in 43(57 %) and plain flat foot in 40(53 %). Cardiovascular symptoms occurred in 17(23 %) patients: dyspnea in 10(13 %) and palpitations in 6(8 %). Mitral valve prolapse was observed in 32(43 %) participants and aortic root dilation (z-score ≥ 2) in 53(71 %), without significant difference between the groups with or without these alterations concerning sex, age, or symptom presence. ConclusionClinical profile of a Marfan syndrome outpatient cohort includes adolescents and young adults, most without cardiovascular symptoms and with a high incidence of skeletal, ophthalmological, and cardiovascular involvement. Recognizing these clinical signs could contribute to early disease diagnosis in the general population.

Dystonic Tremor as Main Clinical Manifestation of SCA21.

Spinocerebellar ataxia type 21 (SCA21) is a rare inherited neurological disorder characterized by motor, cognitive, and behavioral disturbances, caused by autosomal dominant TMEM240 variants. To identify the genetic cause of a dystonic tremor with autosomal dominant inheritance. Six subjects of a multi-generational French family affected by tremor and dystonia were studied. Each patient underwent a comprehensive clinical assessment and a whole-exome sequencing analysis. All six subjects presented with early-onset prominent hand dystonic tremor and multifocal/generalized dystonia, secondarily developing mild cerebellar ataxia. The younger generation showed more pronounced cognitive and behavioral impairment. The known pathogenic TMEM240 c.509C>T (p.P170L) variant was found in heterozygosis in all subjects. Dystonic tremor can represent the core clinical feature of SCA21, even in absence of overt cerebellar ataxia. Therefore, TMEM240 pathogenic variants should be considered disease-causing in subjects displaying dystonic tremor, variably associated with ataxia, parkinsonism, neurodevelopmental disorders, and cognitive impairment.

A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations.

Alport syndrome, a rare genetic disorder affecting around 1 in 50,000 individuals, primarily presents as microscopic hematuria and chronic kidney disease (CKD) with associated extrarenal complications. The Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes, disrupting the formation of the α3-α4-α5 chain in the collagen IV network. The etiology involves X chromosome-related, autosomal dominant, autosomal recessive, and digenic inheritance patterns. The disease primarily manifests as kidney involvement, featuring persistent hematuria, proteinuria, and a progressive decline in renal function. Hearing loss, ocular abnormalities, and extrarenal manifestations further contribute to its complexity. Genotype-phenotype correlations are relatively evident, with distinct presentations in X-linked, autosomal recessive, and autosomal dominant cases. Diagnosis relies on urinalysis, histologic examination, and genetic testing with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening. The purpose of this review is to advance knowledge and enhance understanding of Alport syndrome.

Síndrome de Stickler: una causa de oftalmopatía pediátrica

Stickler's syndrome is a rare genetic disease of connective tissue, with dominant autosomal inheritance most of the time. It is characterized by the association of ophthalmopathy (myopia, retinal detachment and cataracts), orofacial abnormalities, hearing loss and arthropathy, with a wide variability in clinical expression. Diagnostic confirmation is obtained by genetic study. The prognosis varies depending on the severity of the manifestations. The absence of an etiological treatment reduces the therapeutic possibilities to a symptomatic treatment that is very often surgical. The importance of knowing its characteristics lies in an early clinical suspicion to try to avoid irreversible sequelae at an early age and provide the family with adequate genetic counseling.

Primary ciliary dyskinesia: a case report of double DNAH11 mutant alleles

Primary ciliary dyskinesia (PCD), a rare disorder, is genetically varied. Mutations in proteins involved in the structure, function, or assembly of cilia are known to determine situs inversus, male infertility, and chronic destructive airway disease. PCD is inherited by an autosomal recessive pattern of inheritance in most cases. Nonetheless, patterns of autosomal dominant and X-linked inheritance have been mentioned. A history of recurrent upper and lower respiratory tract infections raised clinical suspicion of primary ciliary dyskinesia in a 10-year-old patient. Genetic tests were performed using next-generation sequencing technology (Illumina NextGen) with the multiplex ligation-dependent probe amplification technique for primary ciliopathies and syndromes subject to differential diagnosis. Genetic testing identified two pathogenic variants, not previously associated with a case report in the literature, c.7727A&gt;G (p.Asp2576Gly) and c.8578G&gt;A (p.Gly2860Ser), within the DNAH11 gene, which is associated with autosomal recessive PCD. The result also reported mutations in other genes involved in autosomal recessive PCD (DNAH8, DNAH9 and ZMYND10), which were classified as variants with uncertain clinical significance. Transmission electron microscopy of respiratory cilia and nasal nitric oxide measurement cannot be used to diagnose PCD in patients with DNAH11 mutations because the structure of cilia is normal, and the levels of NO are not constantly low. High-speed video microscopy analysis can be helpful because DNAH11 mutations cause a distinct phenotype of PCD. Nevertheless, the mutation analysis of various PCD-causing genes remains the easiest to conduct and with good results. Genetic research on PCD has identified a number of significant ciliary genes in recent years, offering fresh perspectives on the molecular processes underlying cilia assembly and function. This facilitates the development of new methods for the diagnosis, prevention, and treatment of PCD. However, because it is a highly complex and heterogeneous disease, the field of gene diagnosis and therapy in PCD is still in its infancy.

Exploring Preventive Measures and Disease Dynamics of Hereditary Polymorphic Light Eruption in American Indian Children

Hereditary polymorphic light eruption (HPLE) is a condition related to polymorphic light eruption (PLE). Unlike PLE, HPLE is unique to American Indian populations demonstrating autosomal dominant inheritance pattern with incomplete penetrance. Affected individuals possess hypersensitivity to long UV radiation, which heightens the risk for skin damage. Onset is typically childhood and disease severity results in complications including psychosocial trauma, streptococcal pyoderma, and glomerulonephritis. HPLE can be difficult to diagnose due to its overlapping qualities with other conditions, underscoring the importance of accurate diagnosis and management. Preventive measures play critical roles in mitigating disease occurrence and complications. Literature analysis of five articles using PubMed and Google was conducted to understand HPLE among the Native American community, particularly children. Search terms included hereditary polymorphic light eruption, Native Americans, American Indians, polymorphic light eruption, actinic prurigo, UV toxicity, and photosensitivity. Literature delineated the disease process of HPLE and preventive measures. Studies revealed a higher incidence among children/adolescents who presented with rashes within two hours of sun exposure. Rash severity increased as seasons progressed to summertime. It is imperative that affected individuals utilize broad spectrum coverage sunscreen, covering UVA and UVB rays. Other measures proven to be effective include protective clothing, limiting time outdoors during peak sun hours, and using specially formulated lip balm. HPLE creates a unique challenge among American Indian populations necessitating increased awareness and educational strategies to minimize and avoid complications. Providing education on prevention and actively implementing measures can help decrease the complications of HPLE and increase quality of life.

Genetic Basis of Hearing Loss in Mongolian Patients: A Next-Generation Sequencing Study.

The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients. We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns. Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.

A Single-Center Retrospective Cohort Study of Genotype–Phenotype Correlation of Osteogenesis Imperfecta in UAE

Abstract Background Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by skeletal fragility. Patients with OI suffer recurrent fractures, limb deformities, and kyphoscoliosis. Multiple extraskeletal manifestations might also be present. Autosomal dominant variants in the COL1A1 or COL1A2 genes account for approximately 90% of cases. Objective The aim of the study was to describe the variant spectrum and genotype–phenotype correlations in patients with OI seen in Tawam Hospital in the UAE. Methods The authors conducted a retrospective chart review for all patients with OI assessed by geneticists at Tawam Hospital from January 2010 to December 2021. They retrieved each patient's baseline characteristics, detailed history and physical examination, laboratory, imaging, and genetic results. Results A total of 40 patients with OI were found and included in this study. The majority (80%) were Emirati, and 57.5% were females. Consanguinity was documented in 24.3%. Thirty-seven patients (92.5%) had positive molecular testing; 28 patients (75.7%) had an autosomal dominant inheritance, and 9 patients (24.3%) had an autosomal recessive inheritance. The majority had missense variants. Four variants were novel. A high prevalence of pathogenic variants in the COL1A1 gene (57%) was found. Patients with variants in the LEPRE1 gene had early and severe phenotypes, while patients with variants in the TMEM38B gene had variable presentations. The majority of patients (85%) had skeletal phenotypes: fractures, bone deformity, scoliosis, and osteopenia. Extraskeletal phenotypes included blue sclera, dentinogenesis imperfecta, hearing loss, and dysmorphic features. Conclusion This study reports the genotype–phenotype correlation of OI patients from the UAE. A high prevalence of pathogenic variants in the COL1A1 gene with OI type IV phenotype was found. Further multicenter more extensive studies are recommended.

Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report

BackgroundSpinocerebellar ataxia type 1, is a rare neurodegenerative disorder with autosomal dominant inheritance belonging to the polyglutamine diseases. The diagnosis of this disease requires genetic testing that may also include the search for CAT interruption of the CAG repeat tract.Case presentationOne 23-years-old patient suffers from a severe ataxia, with early-onset and rapid progression of the disease. His father might have been affected, but no molecular confirmation has been performed. The genetic results were negative for the Friedreich’s ataxia, spinocerebellar ataxia type 2, 3, 6, 7 and 17. The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats. The patient carried one pathogenic allele of 61 CAG and one intermediate allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted.ConclusionsWe report a rare case of spinocerebellar ataxia type 1 with an intermediate allele and a large SCA1 expansion. The determination of the absence of CAT interruption brought crucial information concerning this molecular diagnosis, the prediction of the disease and had practical consequences for genetic counseling.