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Aim: X‐linked variants in Filamin A (FLNA) are associated with the Ehlers‐Danlos‐syndrome‐variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C‐terminal hydrolase L1 (UCHL1) are associated with a late‐onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole‐gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. Methods: A 67‐year‐old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4‐year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. Results: Neurophysiology including Somatosensory‐evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. Conclusions: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants. [ABSTRACT FROM AUTHOR]

Female carriers of X‐linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease‐causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self‐identified carriers worldwide. Two hundred and twenty‐eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is an incurable X‐linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence‐optimized dystrophin genes driven by muscle‐specific promoters. The four lentiviral vectors stably expressed mini‐dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn‐Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3–6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini‐dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin. [ABSTRACT FROM AUTHOR]

Background and Aims: X‐linked Charcot–Marie–Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea, and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families. Methods: We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole‐exome sequencing in the probands to investigate the genetic basis of the disease. Results: Males in the family carrying the Arg162His mutation displayed early‐onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain. Interpretation: We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co‐segregates with the disease as expected in a X‐linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. [ABSTRACT FROM AUTHOR]

Background: Ornithine transcarbamylase deficiency is an X‐linked genetic disorder that induces accumulation of ammonia in the liver and is the most common urea cycle disorder. The clinical manifestation of ornithine transcarbamylase deficiency is hyperammonemia that causes irreversible neurological damage. Liver transplantation is a curative therapy for ornithine transcarbamylase deficiency. The aim of this study is to suggest, from our previous experience, an anesthesia management protocol of liver transplantation for ornithine transcarbamylase deficiency, particularly focused on liver transplantation for cases with uncontrolled hyperammonemia. Method: We retrospectively reviewed our anesthesia‐related experience in all cases of liver transplantation for ornithine transcarbamylase deficiency in our center. Results: Twenty‐nine liver transplantation cases for ornithine transcarbamylase deficiency were found between November 2005 and March 2021 in our center. Of these, 25 cases were stable through the perioperative period. However, 2 cases with carrier donor graft had hyperammonemia after liver transplantation. Another two cases had uncontrolled hyperammonemia before liver transplantation, even with continuous hemodialysis. They underwent life‐saving liver transplantation. Their metabolic status stabilized after the anhepatic phase. Conclusion: Liver transplantation for cases with uncontrolled hyperammonemia can be performed with proper management. Second, liver transplantation with carrier donors should be avoided because of the risk of postoperative recurrence. [ABSTRACT FROM AUTHOR]

Interestingly, although both patients showed a complete LAMP2 protein deficiency, vacuoles were not visible on light microscopy in the muscle of patient I. This may be due to his young age because the formation of vacuoles and the development of a full picture of DD is a time-dependent process. X-axis shows fold change of mRNA abundance [FPKM] in DD-patients while Y-axis shows fold change of protein abundance (arbitrary units) in patients suffering from DD. Keywords: Danon disease; LAMP2; mitophagy; proteomics; transcriptomics EN Danon disease LAMP2 mitophagy proteomics transcriptomics 1 7 7 09/01/23 20230801 NES 230801 Key points Danon disease is characterised by both vacuolar myopathy and impaired mitochondrial turnover, evident at the morphological, mRNA and protein levels. 184 rows, 5 columns, T-test between DD-patients and Controls p < 0.05 (B) mRNA investigation: DD-patients (n = 2) versus Controls (n = 4) => 14,334 mRNA species included. [Extracted from the article]

Introduction: Incontinentia pigmenti (IP) is a rare X‐linked dominant genetic disease affecting ectodermal tissue and often misdiagnosed in the neonatal period. The aim of this study was to highlight sequential clinical features and evaluate prognosis of the 32 neonatal IP patients. Material and methods: A retrospective descriptive analysis was performed, using the clinical, blood analytical, pathological, radiological, genetic, and followed‐up data of neonatal patients diagnosed with IP from 2010 to 2021, in Xi'an, China. Results: Of the 32 patients, two (6.25%) were male. Thirty babies (93.75%) had eosinophilia (eosinophilic granulocyte count: 0.31–19.9 × 109, mean proportion of white blood cells: 20.98 ± 15.21%). Twenty babies (62.5%) had thrombocytosis (thrombocyte count: 139–975 × 109, mean count: 416.76 ± 176.82). Thirty‐one babies (96.88%) exhibited the first three cutaneous lesion stages characterized by erythema and superficial vesicles on inflammatory bases in a linear distribution in the first week of age. Thirteen babies (40%) combined nervous system abnormalities, and nine babies (28.13%) had retinopathy. Two types of genetic mutations were detected in the NEMO gene. Nineteen babies were followed up. According to the follow‐up, four babies displayed psychomotor retardation, and five babies developed a decrease in vision with astigmatism and amblyopia. Conclusion: It is important that 30 babies (93.75%) had eosinophilia and 20 babies (62.5%) had thrombocytosis. Therefore, we speculate that the mechanism of the injury may be related to the platelet aggregation on the basis of the increase in eosinophil cells and the release of inflammatory factors. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD), the most common muscle degenerative disease, is an X‐linked genetic disorder caused by the loss or reduction of dystrophin protein, resulting in progressive muscle wasting, and involving skeletal, cardiac, and respiratory muscles. There is currently no cure for DMD, and an anti‐inflammatory steroid is the conventional treatment to delay disease progression. Recently, several therapeutic approaches have been developed to improve patient quality of life and even to treat the underlying cause of the disease. These approaches include exon‐skipping, stop‐codon read‐through, vector‐mediated gene therapy, and stem cell transplantation. Exon‐skipping is one of the most promising techniques, and four exon‐skipping drugs have received approval, including NS‐065/NCNP‐01 (viltolarsen) in Japan and the USA. The read‐through drug, Ataluren, has received approval in the EU. Vector‐mediated therapy and cell transplantation are also attractive approaches, and currently, clinical trials are ongoing for some drugs. Furthermore, several studies have developed innovative approaches for DMD treatment, such as multiple exon skipping, gene editing using the CRISPR/Cas9 system, and mesenchymal stromal cell (MSC)‐ or inducible pluripotent stem cell (iPSC)‐based cell transplantation. In this review, we summarize current therapeutic approaches for DMD treatment. [ABSTRACT FROM AUTHOR]

Background: Haemophilia is an X-linked recessive genetic disorder characterised by bleeding within soft tissue and joints. The ankle is disproportionally affected by haemarthropathy when compared to the elbows and knees; reported as the most affected joints in patients with haemophilia. Despite advances in treatment, patients still report ongoing pain and disability, however, the impact has not been evaluated, nor has the effect on health-related quality of life (HRQoL) or foot and ankle patient-reported outcome measures (PROMs). The primary aim of this study was to establish the impact of ankle haemarthropathy in patients with severe and moderate haemophilia A and B. Secondly to identify the clinical outcomes associated with a decline in HRQoL and foot and ankle PROMs. Methods: A cross-sectional multi-centre questionnaire study was conducted across 18 haemophilia centres in England, Scotland and Wales with a recruitment target of 245 participants. The HAEMO-QoL-A and Manchester-Oxford Foot Questionnaire (MOXFQ) (foot and ankle) with total and domain scores measured impact on HRQOL and foot and ankle outcomes. Demographics, clinical characteristics, ankle haemophilia joint health scores, multi-joint haemarthropathy and Numerical Pain Rating Scales (NPRS) of "ankle pain over the past six months" were collected as a measure of chronic ankle pain. Results: A total of 243 of 250 participants provided complete data. HAEMO-QoL-A and MOXFQ (foot and ankle) total and index scores indicated worse HRQoL with total scores ranging from a mean of 35.3 to 35.8 (100 best-health) and 50.5 to 45.8 (0 best-health) respectively. NPRS (mean (SD)) ranged from 5.0 (2.6) to 5.5 (2.5), with median (IQR) ankle haemophilia joint health score of 4.5 (1 to 12.5) to 6.0 (3.0 to 10.0) indicating moderate to severe levels of ankle haemarthropathy. Ankle NPRS over six months and inhibitor status were associated with decline in outcome. Conclusions: HRQoL and foot and ankle PROMs were poor in participants with moderate to severe levels of ankle haemarthropathy. Pain was a major driver for decline in HRQoL and foot and ankle PROMs and use of NPRS has the potential to predict worsening HRQoL and PROMs at the ankle and other affected joints. [ABSTRACT FROM AUTHOR]

Background: Wiedemann–Steiner syndrome (WSS) is a rare genetic disorder caused by heterozygous variants in KMT2A. To date, the cognitive profile associated with WSS remains largely unknown, although emergent case series implicate increased risk of non‐verbal reasoning and visual processing deficits. This study examines the academic and learning concerns associated with WSS based on a parent‐report screening measure. Participants and Methods: A total of 25 parents of children/adults with a molecularly‐confirmed diagnosis of WSS (mean age = 12.85 years, SD = 7.82) completed the Colorado Learning Difficulties Questionnaire (CLDQ), a parent‐screening measure of learning and academic difficulties. Parent ratings were compared to those from a normative community sample to determine focal areas in Math, Reading and Spatial skills that may be weaker within this clinical population. Results: On average, parent ratings on the Math (mean Z = ‐3.08, SD = 0.87) and Spatial scales (mean Z = ‐2.52, SD = 0.85) were significantly more elevated than that of Reading (mean Z = ‐1.31, SD = 1.46) (Wilcoxon sign rank test Z < −3.83, P < 0.001), reflecting relatively more challenges observed in these areas. Distribution of parent ratings in Math items largely reflect a positively skewed distribution with most endorsing over three standard deviations below a community sample. In contrast, distributions of parent ratings in Reading and Spatial domains were more symmetric but flat. Ratings for Reading items yielded much larger variance than the other two domains, reflecting a wider range of performance variability. Conclusions: Parent ratings on the CLDQ suggest more difficulties with Math and Spatial skills among those with WSS within group and relative to a community sample. Study results are consistent with recent case reports on the neuropsychological profile associated with WSS and with Kabuki syndrome, which is caused by variants in the related gene KMT2D. Findings lend support for overlapping cognitive patterns across syndromes, implicating potential common disease pathogenesis. [ABSTRACT FROM AUTHOR]

Aims: Fabry disease (FD) is a rare X‐linked genetic disorder caused by α‐galactosidase A (AGALA) deficiency. Whereas 'classic' variant has multisystemic manifestation, the more recently described 'later‐onset' variant is characterized by predominant cardiac involvement that often mimics hypertrophic cardiomyopathy (HCM). Methods and results: Consecutive unrelated patients with HCM were screened for FD in 16 (out of 17) cardiac centres in the Czech Republic covering specialized cardiology care from June 2017 to December 2018. AGALA activity and globotriaosylsphingosine (lyso‐Gb3) levels were measured in all subjects using the dry blood spot method. FD was suspected in male patients with AGALA activity <1.2 μmol/h/L and in females with either low AGALA activity or lyso‐Gb3 > 3.5 ng/mL. Positive screening results were confirmed by genetic testing. We evaluated 589 patients (390 males, 66%) with HCM (mean maximal myocardial thickness 19.1 ± 4.3 mm). The average age was 58.4 ± 14.7 years. In total, 17 patients (11 males, 6 females) had a positive screening result, and subsequently, six of them (four males and two females) had a genetically confirmed pathogenic GLA mutation (total prevalence of 1.02%). Five of these patients were carrying the p.N215S mutation known to cause a typical later‐onset cardiac FD. Conclusions: We confirmed the prevalence of FD repeatedly reported in previous screening programmes (approximately 1% irrespective of gender) in a non‐selected HCM population in Central Europe. Our findings advocate a routine screening for FD in all adult patients with HCM phenotype including both genders. The dry blood spot method used led to identification of clearly pathogenic variants. [ABSTRACT FROM AUTHOR]

The article offers information about the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome and disease taxonomy in rheumatology. It mentions that VEXAS syndrome, discovered through the use of a genotype-first approach, whereby a large genetic database was analyzed for commonalities among patients, with minimal consideration of clinical phenotype.

X‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) disease is one of the most common subtypes of inherited neuropathies and is caused by mutations in the GJB1 gene. To date, more than 400 mutations have been reported in GJB1 worldwide but none in sub‐Saharan Africa (SSA). We aimed to clinically characterize patients with CMTX1 and identify the genetic defects. All patients were examined thoroughly, and Nerve Conduction Studies (NCS) were done. EEG and pure tone audiometry (PTA) were also done in select individuals having additional symptoms. DNA was extracted for CMT gene panel testing (50 genes + mtDNA and PMP22 duplication), and putative variants were screened in available relatives. The predominant starting symptom was tingling, and the chief complaint was gait difficulty. Neurological examination found a distal muscle weakness and atrophy, and sensory loss, skeletal deformities, decreased or absent reflexes and steppage gait. The inheritance pattern was consistent with dominant X‐linked. NCS showed no response in most of the tested nerves in lower limbs, and normal or reduced amplitudes in upper limbs. A severe sensorineural hearing impairment and a focal epileptic seizure were observed in one patient each. A high intra and inter‐familial clinical variability was observed. Genetic testing found three pathogenic missense variants in GJB1, one in each of the families (Val91Met, Arg15Trp, and Phe235Cys). This is the first report of genetically confirmed cases of CMTX1 in SSA, and confirms its clinical and genetic heterogeneity. [ABSTRACT FROM AUTHOR]

Epilepsy is a nervous system disease caused by abnormal discharge of brain neurons, which is characterized by recurrent seizures. The factors that induce epilepsy include genetic and environmental factors. Genetic factors are important pathogenic factors of epilepsy, such as epilepsy caused by protocadherin‐19 (PCDH‐19) mutation, which is an X‐linked genetic disease. It is more common in female heterozygotes, which are caused by mutations in the PCDH‐19 gene. Epilepsy caused by environmental factors is mainly caused by brain injury, which is commonly caused by brain tumors, brain surgery, or trauma to the brain. In addition, the pathogenesis of epilepsy is closely related to abnormalities in some signaling pathways. The Wnt/β‐catenin signaling pathway is considered a new target for the treatment of epilepsy. This review summarizes these factors inducing epilepsy and the research hypotheses regarding the pathogenesis of epilepsy. The focus of this review centers on cadherins and the pathogenesis of epilepsy. We analyzed the pathogenesis of epilepsy induced by N‐cadherin and PCDH‐19 in the cadherin family members. Finally, we expect that in the future, new breakthroughs will be made in the study of the pathogenesis and mechanism of epilepsy at the cellular and molecular levels. Key points: The factors that induce epilepsy include genetic and environmental factors.Genetic factors are important pathogenic factors of epilepsy, such as epilepsy caused by protocadherin‐19 (PCDH‐19) mutation, which is an X‐linked genetic disease.Epilepsy caused by environmental factors is mainly caused by brain injury, which is commonly caused by brain tumors, brain surgery, or trauma to the brain. [ABSTRACT FROM AUTHOR]

We describe two brothers with a recurrent truncating EIF2S3 variant and MEHMO (Mental retardation, Epileptic seizures, Hypogonadism and ‐genitalism, Microcephaly, Obesity). Both had the previously described facial dysmorphic features, microcephaly, developmental impairment, hypoglycemia, hypothyreosis, diabetes mellitus, epilepsy, hypertonus, obesity, and micropenis. Additionally, we describe hypothermia and reduced umbilical blood flow. [ABSTRACT FROM AUTHOR]

Preconception carrier screening allows identification of couples at risk to have offspring with autosomal recessive and X-linked disorders. In a current multiethnic world, screening based on self-reported ancestry has limitations. Here we describe the findings of a comprehensive pan-ethnic variant-based carrier screening, using the Israeli Jewish population as a model. The cohort included 1696 individuals (848 couples) tested with the ‘MyScreen’ multigene panel. The panel covers 1206 variants spanning 385 genes, known in different Jewish ethnicities and local Arab, Druze and Bedouin populations. Out of these, 205 variants in 143 genes are Jewish founder variants. We identified 859 (50.6%), carriers of at least one variant in 151 genes. Importantly, 569 (66.2%) of carriers could be missed by the current Israeli screening program. In total, 1:40 (2.5%) of carrier couples were identified by the ‘MyScreen’ panel, compared with 1:144 (0.7%) found by the ethnicity-based screening. Surprisingly, 90 individuals (10.5%) were carriers of variants “unexpected” for their reported origin, and 16 variants were previously unreported in Jewish patients. Our results support the advantages of variant-based comprehensive carrier screening for detection of carriers and at-risk couples in a diverse population with many founder disease-causing variants. [ABSTRACT FROM AUTHOR]

Incontinentia pigmenti (IP) is a rare X-linked dominant genetic disorder caused by mutations in I IKBKG i gene with multisystemic anomalies including cutaneous, dental, ocular and neurological.1 Skin is the most commonly affected organ in IP, presenting at birth or in the first few weeks of life with a vesicobullous eruption.1 The vesicobullous stage, after evolving through verrucous and hyperpigmented phases during infancy, may leave subtle hypopigmented/atrophic patches and usually remains quiescent thereafter throughout life. Recurrence of vesicular stage lesions in an adult female patient with incontinentia pigmenti-including molecular analysis Case report A 31-year-old Thai female patient presented with vesicular eruptions localised on the trunk and extremities occurring 1 month after an episode of fever, nasal obstruction and dry cough. [Extracted from the article]

Fabry disease (FD) is an X‐linked genetic disease due to pathogenic variants in GLA. The phenotype varies depending on the GLA variant, alpha‐galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non‐pathogenic variants or variants of unknown significance (VUS). This, together with the non‐specificity of some FD symptoms, challenges physicians attempting to interpret GLA variants. The traditional way to interpreting pathogenicity is based on a combined approach using allele frequencies, genomic databases, global and disease‐specific clinical databases, and in silico tools proposed by the American College of Medical Genetics and Genomics. Here, a panel of FD specialists convened to study how expertise may compare with the traditional approach. Several GLA VUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr, p.Asp313Tyr), were re‐analyzed through reviews of patients' charts. The same was done for pathogenic GLA variants with some specificities. Our data suggest that input of geneticists and physicians with wide expertise in disease phenotypes, prevalence, inheritance, biomarkers, alleles frequencies, disease‐specific databases, and literature greatly contribute to a more accurate interpretation of the pathogenicity of variants, bringing a significant additional value over the traditional approach. [ABSTRACT FROM AUTHOR]

The article presents a case study of a six-year-old boy with X-linked inhibitor of apoptosis protein (XIAP) deficiency, a rare immune disorder. Topics discussed include the XIAP deficiency characteristics, challenges in conventional treatments, and the success of alemtuzumab-based conditioning in preventing complications during transplantation.

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three-dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR-Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

Background: Nance‐Horan syndrome (NHS) is a rare X‐linked genetic disorder characterized by ophthalmologic and dental anomalies as well as dysmorphic facies. The clinical phenotype in males includes congenital cataracts, vision loss, microcornea, nystagmus, microphthalmia, glaucoma, screwdriver blade‐shaped incisors, supernumerary maxillary incisors, diastema, delays, intellectual disability, and dysmorphic facies. With the evolution of array‐CGH technology, a total of five kindreds with NHS have been reported in the medical literature with microdeletions encompassing the NHS gene rather than sequencing variants. Methods: The patient is a 19‐year‐old male born to non‐consanguineous parents with a past medical history of bilateral congenital cataracts, nystagmus, poor vision, glaucoma, screwdriver blade‐shaped incisors, global developmental delay, intellectual disability, bilateral sensorineural hearing loss, axial hypotonia, and bilateral foot contractures. Results: A chromosomal microarray (CMA) was performed and revealed a 1.83‐Mb interstitial microdeletion at Xp22.2p22.13 (16,604,890–18,435,836) (GRCh37/hg19) that included NHS, CTPS2, S100G, TXLNG, RBBP7, REPS2, SCML1, RAI2, and SCML2. Conclusion: Here, we report the second largest microdeletion causative of NHS which also encompasses the remaining four kindreds in hopes of offering a unique perspective at the clinical variability within NHS, investigate genes of interest, and expand the phenotype. [ABSTRACT FROM AUTHOR]

Early clinical trials of therapies to treat Duchenne muscular dystrophy (DMD), a fatal genetic X‐linked pediatric disease, have been designed based on the limited understanding of natural disease progression and variability in clinical measures over different stages of the continuum of the disease. The objective was to inform the design of DMD clinical trials by developing a disease progression model‐based clinical trial simulation (CTS) platform based on measures commonly used in DMD trials. Data were integrated from past studies through the Duchenne Regulatory Science Consortium founded by the Critical Path Institute (15 clinical trials and studies, 1505 subjects, 27,252 observations). Using a nonlinear mixed‐effects modeling approach, longitudinal dynamics of five measures were modeled (NorthStar Ambulatory Assessment, forced vital capacity, and the velocities of the following three timed functional tests: time to stand from supine, time to climb 4 stairs, and 10 meter walk‐run time). The models were validated on external data sets and captured longitudinal changes in the five measures well, including both early disease when function improves as a result of growth and development and the decline in function in later stages. The models can be used in the CTS platform to perform trial simulations to optimize the selection of inclusion/exclusion criteria, selection of measures, and other trial parameters. The data sets and models have been reviewed by the US Food and Drug Administration and the European Medicines Agency; have been accepted into the Fit‐for‐Purpose and Qualification for Novel Methodologies pathways, respectively; and will be submitted for potential endorsement by both agencies. [ABSTRACT FROM AUTHOR]

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X‐linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic‐pharmacodynamic (PK‐PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK‐PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first‐order absorption, 1‐compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK‐PD parameters. No other intrinsic factors affected PK or PK‐PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data. [ABSTRACT FROM AUTHOR]

The article informs that Glucose-6-phosphate dehydrogenase (G6PD) function is deficient, there is insufficient NADPH production for detoxification when the production of reactive oxygen species (ROS) increases, which contributes to oxidative damage and early hemolysis. It mentions G6PD activity during red cell storage under standard blood bank conditions.

Background: Recent large‐scale initiatives have led to systematically collected phenotypic data for several rare genetic conditions implicated in autism spectrum disorder (ASD). The onset of developmentally expected skills (e.g. walking, talking) serve as readily quantifiable aspects of the behavioral phenotype. This study's aims were: (a) describe the distribution of ages of attainment of gross motor and expressive language milestones in several rare genetic conditions, and (b) characterize the likelihood of delays in these conditions compared with idiopathic ASD. Methods: Participants aged 3 years and older were drawn from two Simons Foundation Autism Research Initiative registries that employed consistent phenotyping protocols. Inclusion criteria were a confirmed genetic diagnosis of one of 16 genetic conditions (Simons Searchlight) or absence of known pathogenic genetic findings in individuals with ASD (SPARK). Parent‐reported age of acquisition of three gross motor and two expressive language milestones was described and categorized as on‐time or delayed, relative to normative expectations. Results: Developmental milestone profiles of probands with genetic conditions were marked by extensive delays (including nonattainment), with highest severity in single gene conditions and more delays than idiopathic ASD in motor skills. Compared with idiopathic ASD, the median odds of delay among the genetic groups were higher by 8.3 times (IQR 5.8–16.3) for sitting, 12.4 times (IQR 5.3–19.5) for crawling, 26.8 times (IQR 7.7–41.1) for walking, 2.7 times (IQR 1.7–5.5) for single words, and 5.7 times (IQR 2.7–18.3) for combined words. Conclusions: Delays in developmental milestones, particularly in gross motor skills, are frequent and may be among the earliest indicators of differentially affected developmental processes in specific genetically defined conditions associated with ASD, as compared with those with clinical diagnoses of idiopathic ASD. The possibility of different developmental pathways leading to ASD‐associated phenotypes should be considered when deciding how to employ specific genetic conditions as models for ASD. [ABSTRACT FROM AUTHOR]

Keywords: vacuoles; myelodysplastic syndromes; ubiquitin-activating enzymes; VEXAS syndrome; autoinflammatory disorder EN vacuoles myelodysplastic syndromes ubiquitin-activating enzymes VEXAS syndrome autoinflammatory disorder 286 289 4 10/12/21 20211015 NES 211015 VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described adult-onset inflammatory disease,1 responsible for inflammatory and haematological disorders.2 The presence of bone marrow vacuoles appeared to be greatly significant in the diagnosis of VEXAS syndrome.1 However, myeloid and erythroid vacuolization has been described in other disorders: copper deficiency,3 acute myeloid leukaemia,4 Menkès disease5 and transcobalamin II deficiency.6 Nevertheless, these disorders are not associated with chronic inflammatory signs. Vacuoles, myelodysplastic syndromes, ubiquitin-activating enzymes, autoinflammatory disorder, VEXAS syndrome Vacuoles in neutrophil precursor cells in bone marrow analysis of a patient in the VEXAS group (A) and a patient in the MDS group (B).Table SI. [Extracted from the article]

Barth syndrome (BTHS) is a rare X‐linked genetic disorder caused by mutations in the gene encoding the transacylase tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial oxidants have been implicated in the cardiomyopathy in BTHS. Eleven mitochondrial sites produce superoxide/hydrogen peroxide (H2O2) at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2O2 production from each site and the ex vivo rate of superoxide/H2O2 production in the heart and skeletal muscle mitochondria of the tafazzin knockdown mice (tazkd) from 3 to 12 months of age. Despite reduced oxidative capacity, superoxide/H2O2 production was indistinguishable between tazkd mice and wild‐type littermates. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology. [ABSTRACT FROM AUTHOR]

X‐linked hypophosphataemia (XLH) and osteogenesis imperfecta (OI) are rare congenital disorders characterised by skeletal dysplasia. The two disorders may include dental anomalies potentially affecting individual well‐being. The aims of study were (a) to assess the oral health‐related quality of life (OHRQoL) in Danish adults with XLH or OI, and (b) to compare the results of the groups. A cross‐sectional study including 35 adults with XLH, 56 adults with OI type I and 17 adults with OI types III‐IV was conducted. The OHRQoL was assessed by the 49‐item version of the questionnaire Oral Health Impact Profile (OHIP). Summed domain scores (seven) were compared between XLH and OI groups. Prevalence of severe impact on OHRQoL (scores 3‐4) was compared between groups. The median scores in XLH group exceeded the medians in OI (P <.05) in the domains functional limitation (XLH:6.5; OI:4.0), pain (XLH:9.5; OI:5.0), psychological discomfort (XLH:5.5; OI:2.0), psychological disability (XLH:2.0; OI:0.0), handicap (XLH:2.0; OI:0.0) and total OHIP (XLH:35.0; OI:14.0). Differences in domains physical disability (XLH: 4.0; OI: 1.0) and social disability (XLH: 0.0; OI: 0.0) were not significant. Prevalence of severe impact on OHRQoL in the XLH group significantly exceeded the level in OI group in the domains functional limitation (XLH: 59%; OI: 35%), psychological discomfort (XLH: 38%; OI: 20%) and physical disability (XLH: 32%; OI: 13%). In conclusion, adults with XLH experience a higher negative impact on their OHRQoL than adults with OI. Only to a minor degree, individuals with OI types III‐IV experience a higher impact on OHRQoL than individuals with OI type I. [ABSTRACT FROM AUTHOR]

Background: Ultrarare Marshall–Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross‐sectional study, and results are presented with genetic findings. Methods: Behavioural phenotypes are compared of eight individuals with Marshall‐Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long‐term follow‐up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall–Smith syndrome. Results: Marshall–Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow‐up measurement of cognition and adaptive behaviour in Marshall–Smith syndrome shows different individual learning curves over time. Conclusions: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person‐environment fit. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory dermatosis with complex genetic basis supported by family investigation. Renal involvement in psoriasis is sparsely studied and its pathogenesis is still unclear. Methods and Results: We describe the case of a 7‐year‐old boy presented new onset of nephropathy two weeks after a flare‐up of psoriasis. His mother had a long history of psoriasis without abnormal urinalysis records. The case showed non‐nephrotic range proteinuria, microscopic hematuria without any other abnormal results including renal function, complement cascade, and ultrasound. Renal pathological demonstrated the diagnosis of C3 glomerulonephritis (C3GN) showing mesangial proliferative glomerulonephritis with C3 staining only, effacement of podocyte process and intramembranous electron dense deposit by electric microscopy. Parent‐child trio WES performed to screening the common variants of psoriasis susceptibility locus and also the rare variants associated with C3GN. We identified a missense single nucleotide polymorphism of CARD14 (*607211, rs34367357, p.Val585Ile) carried by the proband and his mother. Meta‐analysis proved the association of rs34367357 and psoriasis (p = 0.006, OR = 1.23). A hemizygouse mutation of CLCN5 (*300008, c.1904A＞G,p.Asn635Ser) was identified for diagnosis of Dent disease (*300009). Conclusion: The case highlights the genetic study is necessary to facilitate disease differentiation in new onset of nephropathy with psoriasis in children. [ABSTRACT FROM AUTHOR]

Background: Incontinentia pigmenti (IP) is a rare multisystemic X‐linked dominant genetic disorder characterized by highly diagnostic skin lesions. The disease can be misdiagnosed in infants, and complications affecting the eyes and/or the brain can be severe. Our objective was to highlight the urgency of an appropriate diagnosis and management strategy, as soon as the first symptoms appear, and the need for a well‐codified monitoring strategy for each child. Methods: An in‐depth literature review using a large number of databases was conducted. The selection criteria for articles were literature review articles on the disease, case series and retrospective studies based on the disease, clinical studies (randomized or not) on treatment, articles discussing patient care and management (treatment, diagnosis, care pathways), and recommendations. The research period was from 2000 until 2018. A group of multidisciplinary experts in IP management was involved, issued from different healthcare providers of the European Network for Rare Skin Diseases (ERN‐Skin). The final recommendations have been submitted to two patient representative associations and to a general practitioner and a neonatal specialist prior to their finalization. Results and conclusion: The diagnosis of IP must be promptly performed to detect potential extracutaneous manifestations, thus allowing the timely implementation of specific therapeutic and monitoring strategies. Eye involvement can be a therapeutic urgency, and central nervous system (CNS) involvement requires a very rigorous long‐term follow‐up. Assessments and patient support should take into account the possible co‐occurrence of various symptoms (including motor, visual and cognitive symptoms). [ABSTRACT FROM AUTHOR]

The homology‐independent targeted integration (HITI) strategy enables effective CRISPR/Cas9‐mediated knockin of therapeutic genes in nondividing cells in vivo, promising general therapeutic solutions for treating genetic diseases like X‐linked juvenile retinoschisis. Herein, supramolecular nanoparticle (SMNP) vectors are used for codelivery of two DNA plasmids—CRISPR‐Cas9 genome‐editing system and a therapeutic gene, Retinoschisin 1 (RS1)—enabling clustered regularly interspaced short palindromic repeats (CRISPR)‐associated protein 9 (CRISPR/Cas9) knockin of the RS1 gene with HITI. Through small‐scale combinatorial screenings, two SMNP vectors, with Cas9 and single guide RNA (sgRNA)‐plasmid in one and Donor‐RS1 and green fluorescent protein (GFP)‐plasmid in the other, with optimal delivery performances are identified. These SMNP vectors are then employed for CRISPR/Cas9 knockin of RS1/GFP genes into the mouse Rosa26 safe‐harbor site in vitro and in vivo. The in vivo study involves intravitreally injecting the two SMNP vectors into the mouse eyes, followed by repeated ocular imaging by fundus camera and optical coherence tomography, and pathological and molecular analyses of the harvested retina tissues. Mice ocular organs retain their anatomical integrity, a single‐copy 3.0‐kb RS1/GFP gene is precisely integrated into the Rosa26 site in the retinas, and the integrated RS1/GFP gene is expressed in the retinas, demonstrating CRISPR/Cas9 knockin of RS1/GFP gene. [ABSTRACT FROM AUTHOR]

In this essay, I recount and examine my response to a genetic diagnosis of my disabled daughter. My daughter was forty‐nine before the diagnosis came. All her disabilities were traceable to a de novo single gene variant on the PURA gene that was discovered only in 2014. I speak of the jolt and the recalibration that this discovery engendered, concluding that, while it seemed that everything had changed, nothing had changed. But my family did discover a community in which Sesha joins other PURA‐perfect sons and daughters and where we as a family acquire a "horizontal identity" marked by a genetic variant. [ABSTRACT FROM AUTHOR]

Mutations in apoptosis‐inducing factor mitochondrion‐associated‐1 (AIFM1) cause X‐linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described. We describe a large Irish family with seven affected males. They presented with a variable age of onset, 18 months to 39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia, and pyramidal involvement. In addition, three had colour vision deficiency. Scale for the assessment and rating of ataxia ranged 2 to 23/40, while Charcot‐Marie‐Tooth neuropathy score 2 varied between 7 and 13/36. All individuals had normal cognitive assessment. Neurophysiology demonstrated length‐dependent large‐fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Four obligate female carriers were assessed clinically, two of them neurophysiologically; all were unaffected. Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative. AIFM1‐associated phenotype in this family demonstrated significant variability. To our knowledge, this is the first report of AIFM1‐associated colour blindness. Superficial radial nerve was particularly affected neurophysiologically, which could represent a phenotypic marker towards this specific genetic diagnosis. [ABSTRACT FROM AUTHOR]

Placental mesenchymal dysplasia (PMD), characterized by an enlarged and thickened placenta with multiple hypoechoic cystic spaces, frequently leads to a poor infantile/fetal outcome. Here, we describe a case of PMD involving an infant delivered at term with a good outcome. The fetus was male, and the proportion of the PMD lesion to the entire placenta remained constant: the PMD lesion did not enlarge. Given what is known about the pathogenesis of PMD with its association with vascular endothelial growth factor‐D (VEGF‐D) encoded by an X‐linked gene and androgenetic/biparental mosaicism, which is consistent with female dominancy and a poor outcome, we suggest that a male sex of the fetus and non‐progressing PMD may have been associated with this good outcome. [ABSTRACT FROM AUTHOR]

This review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones. [ABSTRACT FROM AUTHOR]

Aim: In this study, a questionnaire survey was conducted to find the relationship between preeclampsia (PE) and incontinentia pigmenti (IP). Methods: Using a questionnaire survey of 147 women whose children were diagnosed with IP, this study first investigated their clinical manifestations and complications during pregnancy. The manifestations included high blood pressure, proteinuria and edema after 20 weeks of gestation. Women with and without IP were separated into two groups, then analyzed accordingly. Results: There were 45 mothers with IP in the case group and 102 mothers without IP in the control group. IP mothers who were pregnant with an IP fetus were at higher risk for hypertension, proteinuria, and edema during pregnancy as compared with non‐IP mothers that carried an IP fetus. Out of these 147 mothers, 8 mothers with IP and 6 mothers without IP presented with new‐onset hypertension during pregnancy (P = 0.024)，7 mothers with IP and 4 mothers without IP presented with new‐onset proteinuria during pregnancy (P = 0.013)，and 21 IP mothers and 27 non‐IP mothers presented with edema during pregnancy (P = 0.016). Although no statistical difference was observed, mothers in the case group were more likely to develop the above three symptoms concurrently (6.7% vs 2.0%; P = 0.168), and were more likely to be diagnosed with PE (8.9% vs 3.9%; P = 0.249). Conclusion: Our study revealed that the simultaneous occurrence of IP in the mother and fetus increased the likelihood of clinical manifestations associated with PE during pregnancy. [ABSTRACT FROM AUTHOR]

Mutations in the GJB1 gene are the second most frequent cause of Charcot‐Marie‐Tooth disease (CMT), accounting for approximately 10% of CMT cases worldwide. We retrospectively analyzed detailed clinical and neurophysiological data on four Brazilian families carrying novel mutations of the GJB1 gene. Mutations were identified by bidirectional Sanger sequence analysis on the GJB1 coding region. We identified a total of 12 subjects from four different kindred. There was no male‐to‐male transmission, and their clinical pictures were within the expected spectrum for GJB1‐related neuropathy. Males were more severely affected than females. Five out of the eight females only had subclinical neuropathy. Nerve conduction velocities were in the intermediate range in the male patients and higher in the females affected. These mutations increase the genotypic variability associated with GJB1. [ABSTRACT FROM AUTHOR]

Objective: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP.Methods: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients.Results: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain.Interpretation: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822. [ABSTRACT FROM AUTHOR]

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy. [ABSTRACT FROM AUTHOR]

Summary: X‐linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disease characterized by hypoplasia or absence of hair, teeth and sweat glands. The EDA gene, located on the X chromosome, encodes the type II transmembrane protein ectodysplasin A. Variants in the EDA gene can lead to XLHED in humans, mice, cattle and dogs. In the present study, we investigated a litter of Dachshund puppies, of which four male puppies showed clinical signs of XLHED. We performed a candidate gene analysis in one affected puppy and several non‐affected relatives. This analysis revealed a single base‐pair deletion in the coding sequence of the EDA gene in the affected puppy (NM_001014770.2:c.842delT). The deletion is predicted to cause a frameshift, NP_001014770.1:p.(Leu281HisfsTer22), leading to a premature stop codon which truncates more than one quarter of the EDA protein. Sanger sequencing results confirmed that this variant was inherited from the dam. Based on knowledge about the functional impact of EDA variants in dogs and other species, c.842delT is a convincing candidate causative variant for the observed XLHED in the male puppies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Chronic granulomatous disease (CGD) is an X‐linked (XL) or autosomal recessive (AR) primary immunodeficiency disease. Respiratory burst assessment by flow cytometry is a rapid test of granulocyte stimulation, and results predict the underlying genotype. This study aims to describe the immune‐phenotypic profile of patients with CGD diagnosed in our center and correlate that with underlying genetic mutations. Methods: Immuno‐phenotypic and genetic data on all patients with CGD diagnosed at Sultan Qaboos University Hospital (SQUH) were reviewed. Results: A total of 32 patients were diagnosed with CGD using molecular studies. Genetically confirmed individuals included 1 patient with XL‐CGD (a large deletion involving the CYBB and XK genes resulting in a McLeod phenotype), 27 patients with AR‐CGD with a c.579G>A (p.Trp193X) mutation at the NCF1 gene, and 4 patients with AR‐CGD with a c.784G>A (p.Gly262Ser) mutation at the NCF1 gene. Flow cytometry and molecular results were available for comparison in 26 patients with AR‐CGD. The patients with AR‐CGD had a range of flow cytometry‐generated fluorescent patterns as follows: reduced neutrophil stimulation with a sharp peak (12/26), reduced neutrophil stimulation with a broad peak (11/26), and a complete lack of neutrophil stimulation (3/26). No consistent flow cytometry‐generated fluorescent pattern was observed in either of the 2 AR mutations identified in our patients. Conclusion: Flow cytometry is a robust test of CGD diagnosis. However, results should be interpreted with caution when predicting the underlying probable genotype, and results need to be complemented with definitive molecular studies. [ABSTRACT FROM AUTHOR]

The article present a case study of a 36-year-old mother who had a history of the spontaneous abortion of the male fetus gave birth to a 2,800 g male infant who appeared to be healthy. It mentions the newborn metabolic tests showing a negative result for 3-methylglutaconic aciduria. It also mentions that a vitamin cocktail treatment was initiated to rescue mitochondrial respiration.

Summary: Inhibitor formation is a serious complication of factor VIII (FVIII) replacement therapy for the X‐linked bleeding disorder haemophilia A and occurs in 20%–30% of patients. No prophylactic tolerance protocol currently exists. Although we reported oral tolerance induction using FVIII domains expressed in tobacco chloroplasts, significant challenges in clinical advancement include expression of the full‐length CTB‐FVIII sequence to cover the entire patient population, regardless of individual CD4+ T‐cell epitope responses. Codon optimization of FVIII heavy chain (HC) and light chain (LC) increased expression 15‐ to 42‐fold higher than the native human genes. Homoplasmic lettuce lines expressed CTB fusion proteins of FVIII‐HC (99.3 kDa), LC (91.8 kDa), C2 (31 kDa) or single chain (SC, 178.2 kDa) up to 3622, 263, 3321 and 852 μg/g in lyophilized plant cells, when grown in a cGMP hydroponic facility (Fraunhofer). CTB‐FVIII‐SC is the largest foreign protein expressed in chloroplasts; despite a large pentamer size (891 kDa), assembly, folding and disulphide bonds were maintained upon lyophilization and long‐term storage as revealed by GM1‐ganglioside receptor binding assays. Repeated oral gavages (twice/week for 2 months) of CTB‐FVIII‐HC/CTB‐FVIII‐LC reduced inhibitor titres ~10‐fold (average 44 BU/mL to 4.7 BU/mL) in haemophilia A mice. Most importantly, increase in the frequency of circulating LAP‐expressing CD4+CD25+FoxP3+ Treg in tolerized mice could be used as an important cellular biomarker in human clinical trials for plant‐based oral tolerance induction. In conclusion, this study reports the first clinical candidate for oral tolerance induction that is urgently needed to protect haemophilia A patients receiving FVIII injections. [ABSTRACT FROM AUTHOR]

The article presents a case study of two patients with Simpson-Golabi-Behmel syndrome (SGBS) caused by the loss of-function of the glypican-3 gene (GPC3) and which showed Xq26.2 duplication. It informs about the tandem duplication of GPC3 identified by array comparative genomic hybridization (array-CGH). It also recommends a molecular transcription analysis to assess a possible gene disruption.

Background To identify variants likely responsible for Mendelian disorders among the three major ethnic groups in the Bronx that might be useful to include in genetic screening panels or whole exome sequencing filters and to estimate their likely prevalence in these populations. Methods Variants from a high-density oligonucleotide screen of 192 members from each of the three ethnic-national populations (African Americans, Puerto Ricans, and Dominicans) were evaluated for overlap with next generation sequencing data. Variants were curated manually for clinical validity and utility using the American College of Medical Genetics ( ACMG) scoring system. Additional variants were identified through literature review. Results A panel of 75 variants displaying autosomal dominant, autosomal recessive, autosomal recessive/digenic recessive, X-linked recessive, and X-linked dominant inheritance patterns representing 39 Mendelian disorders were identified among these populations. Conclusion Screening for a broader range of disorders could offer the benefits of early or presymptomatic diagnosis and reproductive choice. [ABSTRACT FROM AUTHOR]

Mutations of human MID1 are associated with X-linked Opitz G Syndrome ( XLOS), which is characterized by midline birth defects. XLOS-observed mutations within the MID1 B-box1 domain are associated with cleft lip/palate, wide-spaced eyes and hyperspadias. Three of the four XLOS-observed mutations in the B-box1 domain results in unfolding but the structural and functional effects of the P151L mutation is not characterized. Here, we demonstrate that the P151L mutation does not disrupt the overall tertiary structure of the B-box1 domain and the adjacent domains. In fact, MID1 E3 ligase activity is slightly enhanced. However, the P151L mutation disrupted the ability of MID1 to catalyze the poly-ubiquitination of alpha4, a novel regulator of PP2A. This observation is consistent with results observed with the other three structure-destabilizing B-box1 mutations in targeting alpha4 but not PP2A. Alpha4 is shown to bind and sequester the catalytic subunit of PP2A and protect it from MID1-mediated ubiquitination and as a result, an increase in alpha4 can contribute to an increase in PP2A, playing a greater role in midline development during embryogenesis. [ABSTRACT FROM AUTHOR]

Objectives European ancestry in many populations in Latin America at autosomal loci is often higher than that from X-linked loci indicating more European male ancestry and more Amerindian female ancestry. Generally, this has been attributed to more European male gene flow but could also result from an advantage to European mating or reproductive success. Methods Population genetic models were developed to investigate the dynamics of gene flow and mating or reproductive success. Using estimates of autosomal and X-chromosome European ancestry, the amount of male gene flow or mating or reproductive advantage for Europeans, or those with European ancestry, was estimated. Results In a population from Antioquia, Colombia with an estimated 79% European autosomal ancestry and an estimated 69% European X-chromosome ancestry, about 15% male gene flow from Europe or about 20% mating or reproductive advantage of Europeans over Amerindians resulted in these levels of European ancestry in the contemporary population. Combinations of gene flow and mating advantage were nearly additive in their impact. Conclusions Gene flow, mating advantage, or a combination of both factors, are consistent with observed levels of European ancestry in a Latin American population. This approach provides a general methodology to determine the levels of gene flow and mating differences that can explain the observed contemporary differences in ancestry from autosomes and X-chromosomes. [ABSTRACT FROM AUTHOR]