Autosomal Dominant Inheritance Research Articles

Lynch syndrome

Patients with Lynch syndrome, one of the most common hereditary tumor predisposition syndromes, harbor an increased risk for abroad spectrum of especially gastrointestinal and gynecological tumors. Causative for the syndrome are variants in DNA mismatch repair genes, which are passed on to the offspring at a50% chance (autosomal dominant inheritance). The tumor tissue of these patients usually shows microsatellite instability, which is of increasing relevance regarding prognosis and therapeutic decisions. The detection of acausative genetic variant in apatient enables predictive testing of family members to provide relief to noncarriers and provide carriers with intensified risk-adapted surveillance. In addition, chemoprevention with aspirin (acetylsalicylic acid) has been proven useful for chemoprevention in studies. Therefore, the diagnosis of Lynch syndrome is important for patients and their relatives.

POT1 tumour predisposition: a broader spectrum of associated malignancies and proposal for additional screening program

Protection of Telomeres Protein 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex, regulating telomere length. Some POT1 gene pathogenic variants (PV) lead to telomere elongation, genomic instability and higher risk of cancer. POT1 tumour predisposition syndrome (POT1-TPD) has autosomal dominant inheritance and unknown penetrance. It is associated with increased risk of cutaneous melanoma, chronic lymphocytic leukaemia, angiosarcoma and gliomas. In this work, we aim to describe a broader cancer phenotype related to POT1-TPD, in three families (two with a four generation pedigree, one with a five generation pedigree). The three index cases were referred to our oncogenetic centre for genetic counselling due to their personal history of cancer. Two underwent clinical exome sequencing of 4,867 genes associated with Mendelian genetic diseases, and another underwent gene panel sequencing including POT1, which identified three different POT1 PV: NC_000007.14(NM_015450.2):c.349C>T; NC_000007.14(NM_015450.2):c.233T>C and NC_000007.14(NM_015450.2):c.818G>A; already described in the literature. Referenced relatives, did a target genetic test (according to the POT1 PV identified in the family). In total, 37 individuals were tested (51.4% females), median age of 46 (22–81) years, with POT1 PV detected in 22. POT1-TPD was observed, but also a higher incidence of other cancers (other sarcomas, papillary thyroid cancer, early onset prostate cancer and leukaemia). These findings contribute to an increase in our knowledge about POT1 PV, and it can play a role in the definition of future POT1 PV screening criteria, POT1 carrier surveillance protocols (possibly considering screening for all types of sarcomas) and in genetic counselling.

A novel IRF6 gene mutation impacting the regulation of TGFβ2-AS1 in the TGFβ pathway: A mechanism in the development of Van der Woude syndrome.

Several mutations in the IRF6 gene have been identified as a causative link to VWS. In this investigation, whole-exome sequencing (WES) and Sanger sequencing of a three-generation pedigree with an autosomal-dominant inheritance pattern affected by VWS identified a unique stop-gain mutation-c.748C>T:p.R250X-in the IRF6 gene that co-segregated exclusively with the disease phenotype. Immunofluorescence analysis revealed that the IRF6-p.R250X mutation predominantly shifted its localization from the nucleus to the cytoplasm. WES and protein interaction analyses were conducted to understand this mutation's role in the pathogenesis of VWS. Using LC-MS/MS, we found that this mutation led to a reduction in the binding of IRF6 to histone modification-associated proteins (NAA10, SNRPN, NAP1L1). Furthermore, RNA-seq results show that the mutation resulted in a downregulation of TGFβ2-AS1 expression. The findings highlight the mutation's influence on TGFβ2-AS1 and its subsequent effects on the phosphorylation of SMAD2/3, which are critical in maxillofacial development, particularly the palate. These insights contribute to a deeper understanding of VWS's molecular underpinnings and might inform future therapeutic strategies.

Neoplasia endocrina múltiple

Multiple endocrine neoplasia (MEN) syndromes encompass a heterogeneous group of inherited disorders characterized by a genetic predisposition to developing tumors that mainly affect the endocrine glands. The four recognized syndromes (MEN1, MEN2A, MEN2B, and MEN4) are of autosomal dominant inheritance and are phenotypically distinguished by the development of synchronous or metachronous tumors with varied clinical presentations. Knowing the genetics and progression of each syndrome is useful for determining the tumor detection time frame. Treatments for each manifestation depend on the location, risk of malignancy or recurrence, excess hormones, and surgical morbidity; they require multidisciplinary management.

Hyperekplexia: A Single-Center Experience.

Hyperekplexia is a rare neurogenetic disorder that is classically characterized by an exaggerated startle response to sudden unexpected stimuli. This study aimed to determine clinical and genetic characteristics of our patients with hyperekplexia. The age of onset and diagnosis, familial and perinatal history, clinical course, complications, metabolic screening tests, magnetic resonance imaging (MRI), medications, neuropsychometric evaluations, and gene mutations of patients diagnosed with hyperekplexia were reviewed retrospectively. All hyperekplexia patients had displayed neonatal excessive startle response and muscle stiffness, which we accepted as the major form of the disorder. Sixteen patients had mutations in genes associated with hyperekplexia. The ages at clinical diagnosis and genetic confirmation ranged from newborn to 16 years old and from 2.5 to 19 years, respectively. Nine patients (56.25%) were initially misdiagnosed with epilepsy. Seven patients (43.75%) carried a diagnosis of intellectual disability, defined here as a total IQ <80. Delayed gross motor development was detected in 4 patients (25%), and speech delay was reported in 3 (18.75%). Mutations in GLRA1 (NM_000171.4) and SLC6A5 (NM_004211.5) were identified in 13 (81.25%) and 3 patients (18.75%), respectively. Fifteen of the 16 patients (93.75%) showed autosomal recessive inheritance. Only 1 patient (6.25%) showed autosomal dominant inheritance. Although hyperekplexia is a potentially treatable disease, it can be complicated by delayed speech and/or motor acquisition and also by intellectual disability. This study shows that hyperekplexia is not always a benign condition and that all patients diagnosed with hyperekplexia should be evaluated for neuropsychiatric status and provided with genetic testing.

Molecular basis of hereditary cardiomyopathy: A systematic review

Hereditary cardiomyopathies include a diverse spectrum of myocardial disorders characterized by mechanical and electrical abnormalities, among which hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are distinguished. This paper dives into the genetic foundations of these conditions, with a focus on mutations in genes encoding sarcomere proteins, thin filament proteins, and calcium homeostasis regulators. The familial aggregation of cardiomyopathies underscores the substantial genetic component, with autosomal dominant inheritance patterns predominant in some cases. Genetic testing and counseling emerge as pivotal tools for early diagnosis, risk assessment, and the formulation of personalized treatment strategies. The integration of genetic insights into clinical management holds promise for improving patient outcomes and reducing disease burden. Further analysis of the molecular mechanisms underlying hereditary cardiomyopathies is critical for identifying novel therapeutic targets and advancing precision medicine approaches. By comprehensively exploring the genetic underpinnings of cardiomyopathies, this paper contributes to our understanding of these complex diseases and highlights the potential for innovative interventions to enhance patient care in the field of cardiovascular medicine.

De novo variation in ARID1B gene causes Coffin-Siris syndrome 1 in a Chinese family with excessive early-onset high myopia

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.

#2327 Extent of proteinuria in autosomal dominant Alport syndrome compared to X linked Alport syndrome

Abstract Background and Aims Alport syndrome (AS), as first described by Arthur Cecil Alport in late XIX century, encompasses a clinical picture of neurosensorial hypoacusia, ocular abnormalities, hematuria and proteinuric kidney disease progressing to end-stage kidney disease in the young adulthood. Differently from X-linked and autosomal recessive AS, autosomal dominant AS (ADAS), a more recently recognized entity, whose prevalence based on populational studies may be near to 1%, generally presents with a milder kidney involvement and with negligible extrarenal features. Nevertheless, some of these patients progress to chronic kidney disease (CKD) category G5, with marked intra and interfamilial variability. Although hematuria is almost universally present all three inheritance patterns, the magnitude of proteinuria, a reliable prognostic marker of the X-linked form has not been thoroughly studied in ADAS. We aimed to compare the extent of proteinuria between patients with X-Linked and autosomal dominant AS. Method Retrospective registry data on type of Alport hereditary pattern and spot urine protein to creatinine ratio per CKD category were collected. The 2021 CKD-EPI formula for calculation of glomerular filtration rate (eGFR) was used. Non-parametric test was used to analyze variables that did not follow normal distribution. Results We analyzed proteinuria and eGFR of 127 patients with Alport Syndrome. Information on patient gender, hereditary pattern and gene involved is illustrated it Table 1. Increased proteinuria was observed with CKD progression in all categories (p &amp;lt; 0.05). Within each CKD category, X-linked males had greater median proteinuria followed by, X-linked females and autosomal dominant patients (Table 2 and Fig. 1). No difference in median proteinuria was observed between X-linked females and those with autosomal dominant inheritance throughout CKD categories G1, G2, G4 and G5 (p = 0.142, 0.878, 0.327, 0.909 respectively). Difference in median proteinuria between X-linked females and autosomal dominant inheritance revealed statistical significance in CKD category G3 (p = 0.034), however the small sample size in this group must be taken into account. Conclusion Pathogenic variants in COL4A3, COL4A4, and COL4A5 are all causes of CKD, and proteinuria serves as a hallmark of disease progression. However, the extent of proteinuria in ADAS is significantly lower than that observed in XLAS. Additionally, some ADAS patients develop CKD with only albuminuria. While there is still much to be understood about this common condition, the renal mechanism of damage in ADAS appears to differ definitively from that in XLAS or ARAS.

#3084 Familial nephropathy associated with a combined mutations of Alport and Nail Patella syndrome genes in the same family

Abstract Introduction Alport syndrome is a genetic condition stemming from mutation in Type IV collagen and is characterized by kidney disease and frequently hearing loss and ocular abnormalities. Renal involvement is from an abnormality of the glomerular basement membrane with hematuria and proteinuria progressing eventually to renal failure. In the vast majority, the inheritance is X- linked affecting the alpha 5 chain of type IV collagen while in about 15 percent of the patients the inheritance is autosomal recessive or dominant with mutations affecting alpha 3 or 4 chains of type IV collagen. Sensorineural deafness is common and ocular abnormalities may include lenticonus, corneal opacities, fleck retinopathy and temporal retinal thinning. Nail Patella syndrome (NPS) is a rare genetic condition from mutation in the LMX1B gene on chromosome 9 with an autosomal dominant inheritance. Glomerular disease is from characteristic glomerular basement membrane changes and is associated with nail, pelvic girdle and limb abnormalities. A forme fruste with glomerular lesions but lacking extrarenal features is recognized but uncommon. We present a family with mutations in both COL4A5 and LMX1B presenting with hematuria and proteinuria Case Presentation A 23 year old female was evaluated for hematuria and proteinuria. Her history was notable for kidney biopsy at the age thirteen showing focal and segmental glomerulosclerosis (FSGS). She was treated with tacrolimus for four years from age thirteen through seventeen. Patient was reportedly diagnosed with Nail Patella Syndrome after genetic testing. Her family history was notable for hematuria in her brother and hematuria and proteinuria in her mother. On physical examination she was noted to have no nail or skeletal abnormalities associated with Nail Patella Syndrome. Her labs were notable for a serum creatinine of 0.6 mg/dl and proteinuria of 155 mg/g creatinine of proteinuria. Urine microscopy revealed dysmorphic hematuria. Radiological imaging did not show skeletal abnormalities observed in Nail Patella Syndrome but genetic testing identified a pathogenic variant in COL4A5 c.919G&amp;gt;A (p.Gly307Ser) in addition to a variant of uncertain significance in LMX1B c.349G&amp;gt;A (p.Gly117Ser). Her brother aged 20 had a creatinine of 0.87 mg/dl with dysmorphic hematuria and no proteinuria. Genetic testing showed the same pathogenic variant in COL4A5 as in his sibling. His mother aged 55 was subsequently evaluated and had a creatinine 0.73 mg/dl with dysmorphic hematuria and 152 mg/g of proteinuria. Genetic testing was with the same variant in COL4A5 noted in her two children. Renal biopsy was extensive thinning and segmental lamellation of the glomerular basement membrane with eight percent FSGS. The typical “moth-eaten” appearance of the glomerular basement membrane characteristic of NPS was not evident. Segmental staining was observed with alpha 5 unit of Type IV collagen. Audiology and retinal optical coherence optometry studies are pending. Discussion Alport syndrome and Nail Patella Syndrome are rare genetic disorders that cause variable degrees of renal insufficiency from glomerular base membrane defects and are associated with characteristic extra renal manifestations. This is the first report of an inherited nephritis with combined mutations in COL4A5 and LMX1B. The clinical features and renal biopsy are compatible with Alport Syndrome and the significance of the mutation in LMX1B is uncertain. Conclusion This is the first case report of a combined mutation in COL4A5 and LMX1B gene presenting with hematuria and minimal proteinuria with preserved kidney function.

Mapping cell diversity in human sporadic cerebral cavernous malformations

BackgroundCerebral cavernous malformation (CCM) is a low-flow, bleeding-prone vascular disease that can cause cerebral hemorrhage, seizure and neurological deficits. Its inheritance mode includes sporadic or autosomal dominant inheritance with incomplete penetrance, namely sporadic CCM (SCCM) and familial CCM. SCCM is featured by single lesion and single affection in a family. Among CCM patients especially SCCM, the pathogenesis of the corresponding phenotypes and pathological features or candidate genes have not been fully elucidated yet. MethodsHere, we performed in-depth single-cell RNA sequencing (scRNA-Seq) and bulk assay for transposase-accessible chromatin sequencing (ATAC-Seq) in SCCM and control patients. Further validation was conducted for the gene of interest using qPCR and RNA in situ hybridization (RNA FISH) techniques to provide further atlas and evidence for SCCM generative process. ResultsWe identified six cell types in the SCCM and control vessels and found that the expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 were up-regulated in SCCM tissues. Among the six cell types, we found that compared with control conditions, PVT1 showed a rising peak which followed the pseudo-time axis in endothelial cell clusters of SCCM samples, while showed an increasing trend in smooth muscle cell clusters of SCCM samples. Further experiments indicated that, compared with the control vessels, PVT1 exhibited significantly elevated expression in SCCM samples. ConclusionIn SCCM conditions, We found that in the process of development from control to lesion conditions, PVT1 showed a rising peak in endothelial cells and showed an increasing trend in smooth muscle cells at the same time. Overall, there was a significantly elevated expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 in SCCM specimens compared to control samples.

Autosomal Dominant Weill-Marchesani-Like Syndrome in a Chinese Family due to Novel Haplotypic Mutations in LTBP2

Introduction: Weill-Marchesani syndrome (WMS) is a hereditary connective tissue disorder with substantial heterogeneity in clinical features and genetic etiology, so it is essential to define the full mutation spectrum for earlier diagnosis. In this study, we report Weill-Marchesani-like syndrome (WMS-like) change to autosomal dominance inheritance caused by novel haplotypic mutations in latent transforming growth factor beta-binding protein 2 (LTBP2). Methods: Twenty-five members from a 4-generation Chinese family were recruited from Guangzhou, of whom nine were diagnosed with WMS-like disease, nine were healthy, and seven were of “uncertain” clinical status because of their young age. All members received detailed physical and ocular examinations. Whole-exome sequencing, Sanger sequencing, and real-time PCR were used to identify and verify the causative mutations in family members. Results: Genetic sequencing revealed novel haplotypic mutations on the same LTBP2 chromosome associated with WMS-like, c. 2657C>A/p.T886K in exon 16 and deletion of exons 25–36. Real-time PCR and Sanger sequencing verified both mutations in patients with clinically diagnosed WMS-like, and in one “uncertain” child. In these patients, the haplotypic mutations led to ectopia lentis, short stature, and obesity. Conclusion: Our study revealed that WMS-like may be associated with haplotypic LTBP2 mutations with autosomal dominant inheritance.

Mechanisms of synapse-to-nucleus calcium signalling in striatal neurons and impairments in Huntington's disease.

Huntington's disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor, psychiatric and cognitive disorders. Dysregulated synaptic function and calcium handling are common in many neurodegenerative diseases, including HD. N-methyl-D-aspartate (NMDA) receptor function is enhanced in HD at extrasynaptic sites, altering the balance of calcium-dependent neuronal survival versus death signalling pathways. Endoplasmic reticulum (ER) calcium handling is also abnormal in HD. The ER, which is continuous with the nuclear envelope, is purportedly involved in nuclear calcium signalling; based on this, we hypothesised that nuclear calcium signalling is altered in HD. We explored this hypothesis with calcium imaging techniques, including simultaneous epifluorescent imaging of cytosolic and nuclear calcium using jRCaMP1b and GCaMP3 sensors, respectively, in striatal spiny projection neurons in cortical-striatal co-cultures from the YAC128 mouse model of HD. Our data show contributions from a variety of calcium channels to nuclear calcium signalling. NMDA receptors (NMDARs) play an essential role in initiating action potential-dependent calcium signalling to the nucleus, and ryanodine receptors (RyR) contribute to both cytosolic and nuclear calcium signals. Unlike previous reports in glutamatergic hippocampal and cortical neurons, we found that in GABAergic striatal neurons, L-type voltage-gated calcium channels (CaV) contribute to cytosolic, but not nuclear calcium signalling. Calcium imaging also suggests impairments in nuclear calcium signalling in HD striatal neurons, where spontaneous action potential-dependent calcium transients in the nucleus were smaller in YAC128 striatal neurons compared to those of wild-type (WT). Our results elucidate mechanisms involved in action potential-dependent nuclear calcium signalling in GABAergic striatal neurons, and have revealed a clear deficit in this signalling in HD.

A Unique Clinical Approach to Diagnose a Rare Case of Polycythemia

Primary familial and congenital polycythemia (PFCP) is a rare autosomal dominant disorder caused by hypersensitivity of erythropoetin receptor leading to increased rate of erythropoesis at any given serum erythropoetin level. Thrombosis contributes to severe morbidity and mortality in cases of primary erythrocytosis due to any cause. Primary erythrocytosis or autonomous production of excess erythrocytes occurs mostly due to myeloproliferative neoplasms like polycythemia vera (PV) but can rarely occur in familial conditions also. Even though it does not come under myeloproliferative neoplasm, it can still lead to severe morbidity and early mortality due to increased chances of thrombotic events. However, unlike polycythemia vera, leukemic transformation and myelofibrosis is not seen. Here, we present case of a 33 year old male who presented with both arterial and venous thrombosis and was then diagnosed as non – clonal primary erythrocytosis which was presumably familial as his son was also found to have erythrocytoisis. Diagnosing this fatal condition is essential ; as PFCP has autosomal dominant inheritance and early recognition in family can prevent further vascular events in other family members as well.

TRANSTYRETIN CARDIAC AMYLOIDOSIS IN ELDERLY PATIENTS: ALWAYS A WILD TYPE?

Abstract Background Transthyretin amyloidosis (ATTR) exists in two forms: a genetic form transmitted by autosomal dominant inheritance (ATTRv) and a wild type form (ATTRwt). Clinically, the hereditary form tends to have an early onset in adulthood and it is characterized by a particular tropism for nervous as well as cardiac tissue. In contrast, the "wild type" form has a later onset with major cardiac involvement and neurological manifestations usually limited to carpal tunnel syndrome. Methods and Results In our centre, from September 2021 to June 2023, 52 patients older than 70 years received a diagnosis of cardiac ATTR (87% male, 13% female, mean age 81±5y). In all patients, blood tests showed a significant and stable increase in the values of troponin Ths (0.079 microg/L±0.074) and NT–proBNP (2000±1800 pg/ml), with the absence of a monoclonal component in the blood and urine, and miocardial bisphosphonate scintigraphy positive grade 2/3. All patients underwent genetic testing by amplification of exons 2,3 and 4 of the TTR gene with subsequent sequencing. Unexpectedly, in 10 elderly (70%male, 30% female, mean age 77±4 y) patients (19%) the genetic test resulted positive with 4 different mutations of pathogenetic significance (Val30Met; Ile68Leu; Val142Ile;, Phe84Leu). Three patients showed peripheral neuropathy with the presence of carpal tunnel syndrome, while isolated carpal tunnel syndrome was present in the remaining 7 cases. The three patients with neurologic involvement started Patisiran therapy, and 7 patients were treated with Tafamidis. First–degree relatives (16 consanguineous, average age 49±12 years) agreed to be subjected to genetic screening; of these 9 (3 male and 6 females, age 47±8 years) were positive for the corresponding mutation and underwent echocardiogram, MRI and myocardial scintigraphy. These tests were normal in 8 probands, included in an annual follow–up protocol to identify an early manifestation of the disease, and was diagnostic for amyloidosis in 1 patient who started specific therapy. Conclusions Our experience shows that 19% of patients older than 70 years with a diagnosis of cardiac ATTR may be affected by a genetic form. Making genetic diagnosis in this context is particularly important for screening family members: current therapies are in fact much more effective if started early before organ damage occurs.

Apert Syndrome (Acrocephalosyndactyly): A Rare Case Report

Apert syndrome is the rare acrocephalosyndactyly syndrome, characterized by a classic triad of craniosynostosis, syndactyly of hands and feet, and midfacial hypoplasia. It demonstrates autosomal dominant inheritance attributed to mutations in the fibroblast growth factor receptor gene. Presently described is case of a 18-year-old female patient diagnosed on physical examination with Apert syndrome based on acrocephaly, ocular hypertelorism, frontal bossing, short and broad nose, dental crowding and ectopia, maxillary hypoplasia and bilateral syndactyly of hands and feet. The multiple phenotypic signs of Apert syndrome make multidisciplinary team, including dentist, neurosurgeon, plastic surgeon, physiatrist, ophthalmologist, perinatalogist and geneticist, essential for successful management. Keywords: Apert syndrome, Craniosynostosis, Syndactyly, Midfacial hypoplasia

An adolescent case of ASXL3-related disorder with delayed onset of feeding difficulty

BackgroundASXL3-related disorder, first described in 2013, is a genetic disorder with an autosomal dominant inheritance that is caused by a heterozygous loss-of-function variant in ASXL3. The most characteristic feature is neurodevelopmental delay with consistently limited speech. Feeding difficulty is a main symptom observed in infancy. However, no adolescent case has been reported.Case presentationA 14-year-old girl with ASXL3-related syndrome was referred to our hospital with subacute onset of emotional lability. Limbic encephalitis was ruled out by examination; however, the patient gradually showed a lack of interest in eating, with decreased diet volume. Consequently, she experienced significant weight loss. She experienced no symptoms of bulimia, or food allergy; therefore, avoidant/restrictive food intake disorder (ARFID) was clinically suspected.ConclusionsWe reported the first case of ASXL3-related disorder with adolescent onset of feeding difficulty. ARFID was considered a cause of the feeding difficulty.

Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot-Marie-Tooth disease and identification of H256R as a frequent mutation.

Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot-Marie-Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort. Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected. We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis. In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.

Echocardiography in Hypertrophic Cardiomyopathy

Abstract Hypertrophic cardiomyopathy (HCM) is a common disorder characterized by unexplained left ventricular hypertrophy. The disease can have different phenotypic expressions and can be genetic in nature with autosomal dominant inheritance. It usually runs a benign course in the majority but can lead to heart failure, atrial fibrillation, and sudden cardiac death (SCD). Echocardiography plays a key role in the diagnosis and overall management of the condition. It is useful in diagnosis, differentiation of different types (obstructive vs nonobstructive), in systematic evaluation of associated abnormalities (like mitral regurgitation), helps in selection of appropriate treatment and is helpful in guiding the intervention procedures for the condition. Certain echocardiographic measures are predictors of SCD. The review describes in detail the techniques and nuances of performing a comprehensive echocardiographic evaluation of patients with HCM.

Medial End Clavicular Osteochondroma- An Unusual Case

Abstract Osteochondroma is the most common benign bone tumor, which could present as a sessile or pedunculated type and, in solitary or multiples, hereditary multiple exostoses (a genetic disorder, autosomal dominant inheritance). Clinical presentation is mostly asymptomatic, but if symptomatic, it presents in a wide spectrum, such as compression of adjacent vessels, nerves, deformities, fractures, bursa formation, and malignant transformation. Cancerous transformation is indicated by the thickness of the cartilage cap of &gt;3 cm in children, &gt;2 cm in adults, sudden onset of pain, and sudden/rapid growth of lesion (after growth plate closure). Surgical management is indicated for typical symptomatic lesions, complications, malignant transformation, and cosmetic reasons. The common treatment of choice is the excision of a tumor with a significant free margin.

B-cells absence in patients diagnosed as inborn errors of immunity: a registry-based study.

Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton's agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5-10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in BTK. Three novel mutations in the BTK gene include c.115T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (IGHM) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (CD79A) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (TCF3) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern,which includesa missense variant in PIK3CD, a novel missense variant in PIK3R1 and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (RASGRP1) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.