X-linked Recessive Manner Research Articles

Clinical Features in Boys with Duchenne/Becker Muscular Dystrophy: A Tertiary Center Experience

Background: Dystrophin-related muscular dystrophies are a group of diseases caused by mutations in the dystrophin gene that are inherited in an X-linked recessive manner. Objectives: We aimed to discuss the clinical, laboratory, genetic, treatment, and prognostic features, as well as diagnostic clues, of our DMD/BMD patients. Methods: The medical records of 39 children who were followed up with DMD/BMD diagnoses at Bursa Uludağ University Faculty of Medicine Child Neurology Clinic between August 2018 and September 2023 were evaluated retrospectively. DMD or BMD is diagnosed by genetic testing or muscle biopsy. Results: All patients were male, and the age of symptom onset was 3.44 ± 2.7 years (range: 1 - 12.2 years). Twenty-two cases were symptomatic, presenting with difficulty walking (N = 17), difficulty climbing stairs (N = 14), and getting tired quickly (N = 11). Seventeen cases were initially asymptomatic, identified through elevated CK, AST, and ALT levels. Conclusions: Early recognition that increased serum transaminase and CK levels reflect muscle disease accelerates the diagnosis of underlying conditions and protects patients from unnecessary, invasive, and costly diagnostic testing.

A novel deep intronic variant in the DMD gene causes Duchenne muscular dystrophy by pseudoexon activation encoding a nonsense codon

Dystrophinopathies are a group of neuromuscular disorders, inherited in an X-linked recessive manner, caused by pathogenic variants in the DMD gene. Copy number variation detection and next generation sequencing allow the detection of around 99 % of the pathogenic variants. However, some patients require mRNA studies from muscle biopsies to identify deep intronic pathogenic variants. Here, we report a child suspected of having Duchenne muscular dystrophy, with a muscle biopsy showing dystrophin deficiency, and negative molecular testing for deletions, duplications, and small variants. mRNA analysis from muscle biopsy revealed a pseudoexon activation that introduce a premature stop codon into the reading frame. gDNA sequencing allowed to identified a novel variant, c.832–186 T>G, which creates a cryptic donor splice site, recognizing the underlying mechanism causing the pseudoexon insertion. This case highlights the usefulness of the mRNA analysis from muscle biopsy when routine genetic testing is negative and clinical suspicion of dystrophinopathies remains the main clinical diagnosis suspicion.

B-262 Evaluation of the Genotypic Profile of the c.202 G>A Mutation in the G6PD Gene in Brazil

Abstract Introduction Glucose 6 phosphate dehydrogenase (G6PD) is an enzyme found in the cytoplasm of all human cells and plays an important role in preventing cellular damage to reactive oxygen species (ROS). G6PD deficiency is inherited in an X-linked recessive genetic disorder that can destroy red blood cells (hemolysis) leading to acute hemolytic anemia during periods of increased ROS production. The disease prevalence is more frequent in male individuals. To date, more than 400 G6PD variants have been identified, and molecular studies have shown that G6PD deficiency can be associated with different mutations. The c.202 G > A mutation (rs1050828; NM_000402.4) was described as the most frequent. The rapid and accurate diagnosis of this condition is extremely important in neonatal screening and cases of diagnostic suspicion. Therefore, this study aims to describe the genotypic profile of the c.202 G > A mutation in the G6PD gene in Brazilian samples by two molecular assays. Methods Genomic DNA samples from 130 individuals previously genotyped by Restriction Fragment Length Polymorphism PCR were used for validation. DNA isolation was performed in MagNA Pure 24 Total NA Isolation Kit at the automated platform MagNA Pure 24 System (Roche Diagnostics, Basel, Switzerland), according to manufacturer instructions. Genotyping for rs1050828 was performed using TaqMan SNP Genotyping Assays (Thermo Fisher, Foster City, CA) at 7500 Fast Real-Time PCR System (Thermo Fisher, Foster City, CA), according to manufacturer instructions. The results were analyzed using TaqMan Genotyper Software version 1.0.1. Results This study evaluated 130 blood samples, of which 81 were men (62.3%) and 49 were women (37.7%). Male carriers of rs1050828 A genotype (hemizygotes) predominated (56/81, 69.1%) and the remaining carriers for allele G (wild type) were 25/81 (30.9%). While female carriers of rs1050828 GG (wild type) predominated (39/49, 79.6%), heterozygotes were 5/49 (10.2%), and homozygotes also were 5/49 (10.2%). The number of male individuals with the presence of the mutation in hemi/homozygotes was considerably higher when compared to female individuals. This is explained by the fact that the mutation is inherited in an X-linked recessive manner. The results showed agreement and reproducibility of 100% for both methodologies. However, the qPCR assay sensibility and efficiency (>99%) were higher than the RFLP PCR assay. Conclusions Here, we described an efficient molecular method to detect the mutation c.202 G>A in the G6PD gene. The frequency of c.202 G>A described in this study was similar to that observed in others population studies in Brazil. Detection of the mutation target requests an additional evaluation of the G6PD activity level. Obtained results should be evaluated in association with the clinical aspects. The absence of the c.202 G>A in the G6PD gene does not exclude the existence of other mutations in the same region.

Curated incidence of lysosomal storage diseases from the Taiwan Biobank

Lysosomal storage diseases (LSDs) are a group of metabolic disorders resulting from a deficiency in one of the lysosomal hydrolases. Most LSDs are inherited in an autosomal or X-linked recessive manner. As LSDs are rare, their true incidence in Taiwan remains unknown. In this study, we used high-coverage whole-genome sequencing data from 1,495 Taiwanese individuals obtained from the Taiwan Biobank. We found 3826 variants in 71 genes responsible for autosomal recessive LSDs. We first excluded benign variants by allele frequency and other criteria. As a result, 270 variants were considered disease-causing. We curated these variants using published guidelines from the American College of Medical Genetics and Genomics (ACMG). Our results revealed a combined incidence rate of 13 per 100,000 (conservative estimation by pathologic and likely pathogenic variants; 95% CI 6.92-22.23) to 94 per 100,000 (extended estimation by the inclusion of variants of unknown significance; 95% CI 75.96–115.03) among 71 autosomal recessive disease-associated genes. The conservative estimations were similar to those in published clinical data. No disease-causing mutations were found for 18 other diseases; thus, these diseases are likely extremely rare in Taiwan. The study results are important for designing screening and treatment methods for LSDs in Taiwan and demonstrate the importance of mutation curation to avoid overestimating disease incidences from genomic data.

TOPORS as a novel causal gene for Joubert syndrome.

Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Though over 40 genes have been identified as causal for JBTS, molecular diagnosis is not made in 30%-40% of individuals who meet clinical criteria. TOPORS encodes topoisomerase I-binding arginine/serine-rich protein, and homozygosity for a TOPORS missense variant (c.29C > A; p.(Pro10Gln)) was identified in individuals with the ciliopathy oral-facial-digital syndrome in two families of Dominican descent. Here, we report an additional proband of Dominican ancestry with JBTS found by exome sequencing to be homozygous for the identical p.(Pro10Gln) TOPORS missense variant. Query of the Mount Sinai BioMe biobank, which includes 1880 individuals of Dominican ancestry, supports a high carrier frequency of the TOPORS p.(Pro10Gln) variant in individuals of Dominican descent. Our data nominates TOPORS as a novel causal gene for JBTS and suggests that TOPORS variants should be considered in the differential of ciliopathy-spectrum disease in individuals of Dominican ancestry.

Ayurvedic Emphasis in Duchenne Muscular Dystrophy: A Case Study

Duchenne muscular dystrophy is one of the most common dystrophinopathies known. It is the most common hereditary neuromuscular disorder and is inherited in an X-linked recessive manner. Incidence is 1:3500 live male infants, characterised by progressive weakness of a selective group of muscles without involvement of nervous system. Age of onset being 3-10 years, many children unable to walk before 18 months of age. The patient usually dies by 18-20 years of age. 80% carries have high CPK values with female being the one. Dystrophin gene is the largest human gene with 79 exons, codes for protein dystrophin required for stabilisation of protein complex at sarcolemma, the abnormal DMD gene is on X chromosome at Xp21 locus. Dystrophin deficiency thus, leads to destruction of muscle fibres and progressive muscular weakness. Corticosteroids are the only medications that have shown to alter the course of DMD but have side effects like weight gain, decreased appetite, increase changes of cataract and osteoporosis. The present study is about management 8 years old male child with B/L lower limb weakness and calf muscle hypertrophy.etc, so according to Ayurvedic management with Panchkarma procedures and internal medicines given the case was managed. Successful improvement in CPK values along with the signs and symptoms was observed. As per Ayurvedic Siddhant and Samprapti application considering Adibalapravrittavyadhi and the Beejabhaga avayava dushti the management done. There is no treatment in any system of medicine and prognosis being unpreventable, Ayurveda instills a regenerative mechanism in neuromuscular disorders with special concern of Panchkarma, Rasayanas, Rasa aushadhi, etc. By this the deterioration can effectively be prolonged and quality of life improved.

A novel NONO variant that causes developmental delay and cardiac phenotypes

The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.

Genetic basis of nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus is defined as an inability to concentrate urine due to a complete or partial alteration of the renal tubular response to arginine vasopressin hormone, resulting in excessive diluted urine excretion. Hereditary forms are caused by molecular defects in the genes encoding either of the two main renal effectors of the arginine vasopressin pathway: the AVPR2 gene, which encodes for the type 2 vasopressin receptor, or the AQP2 gene, which encodes for the water channel aquaporin-2. About 90% of cases of nephrogenic diabetes insipidus result from loss-of-function variants in the AVPR2 gene, which are inherited in a X-linked recessive manner. The remaining 10% of cases result from loss-of-function variants in the AQP2 gene, which can be inherited in either a recessive or a dominant manner. The main symptoms of the disease are polyuria, chronic dehydration and hypernatremia. These symptoms usually occur in the first year of life, although some patients present later. Diagnosis is based on abnormal response in urinary osmolality after water restriction and/or administration of exogenous vasopressin. Treatment involves ensuring adequate water intake on demand, possibly combined with thiazide diuretics, non-steroidal anti-inflammatory drugs, and a low-salt and protein diet. In this review, we provide an update on current understanding of the molecular basis of inherited nephrogenic insipidus diabetes.

ODP279 A Case of Nephrogenic Diabetes Insipidus Diagnosed at an Advanced Age in a Female Patient with an AVPR2 Gene Mutation and Skewed×Inactivation

Abstract Background Arginine vasopressin receptor 2 (AVPR2) gene mutationsare the most common cause of congenital nephrogenic diabetes insipidus (CNDI), and they are inherited in an X-linked recessive manner. Women are generally asymptomatic or mildly affected, but atypically severe cases have been reported. Skewed X inactivation, in which the X chromosome is unevenly active, is a cause of this atypical severe case.×chromosome inactivation is a developmental compensation mechanism that results in equal doses of X-linked genes between XX females and XY males and has been reported to be accentuated by aging. Clinical Case A 69-year-old woman had no family history of diabetes insipidus. Immediately after undergoing a craniotomy for subarachnoid hemorrhage in July, she showed marked polyuria of approximately 8000 mL/day and hypernatremia of 161 mEq/L. The use of desmopressin (15mcg/kg/day) did not improve herpolyuria. She was referred to our department in September for further investigation and treatment. Her urine osmolality remained hypotonic at approximately 60–80 mOsm/kg/H 2 O (50–1300 mOsm/kg/H 2 O) according to a water restriction test. Her urine osmolality increased slightly to 106 mOsm/kg/H 2 O in a desmopressin test. These results indicated that desmopressin was ineffective, and the patient was diagnosed with nephrogenic diabetes. Her urine output decreased to approximately 2500 mL/day with trichlormethiazide treatment. There was no significant anterior pituitary hypofunction. Genetic examination revealed a heterozygous mutation of the AVPR2 gene (c.656T>G, p. Leu219Arg) in her X chromosome, and her X chromosome activity ratio was 79: 21 in a human androgen receptor assay, indicating skewed X inactivation. Conclusion We observed a case of CNDI in an elderly woman with no family history of the disease. In this case, a combination of the skewed X inactivation, presumably accentuated by aging, and the onset of subarachnoid hemorrhage, reduced her drinking water and led to the diagnosis of CNDI.

ANOS1 variants in a large cohort of Chinese patients with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). ANOS1, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of ANOS1 in CHH and the relationship between clinical phenotype and genotype. In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of ANOS1 in a Chinese cohort of 165 male CHH patients. Four commonly used in silico tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The ANOS1 genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data. Through WES analysis for 165 CHH patients, ANOS1 RSVs were detected in 17 of them, with the frequency of 10.3%. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p.T76X, p.R191X, p.W257X, p.R262X, and p.W589X), 2 splicing site variants (c.318+3A>C, c.1063-1G>C), and 6 missense variants (p.N402S, p.N155D, p.P504L, p.C157R, p.Q635P, and p.V560I). In these 17 CHH probands with ANOS1 RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p.T76X, p.R191X, p.W257X, p.R262X, p.W589X, c.318+3A>C, c.1063-1G>C, and p.C157R, were predicted to be pathogenic or likely pathogenic ANOS1 RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic ANOS1 variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) ANOS1 variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs. The ANOS1 genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic ANOS1 RSVs tend to exhibit additional phenotypes. Although non-pathogenic ANOS1 variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.

A Novel Form of Familial Vasopressin Deficient Diabetes Insipidus Transmitted in an X-linked Recessive Manner.

Familial pituitary diabetes insipidus has been described only in an autosomal dominant or recessive mode of inheritance. This work aims to determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner. Thirteen members from 3 generations of the kindred with familial DI were studied. Water intake, urine volume, urine osmolality, plasma osmolality, and plasma vasopressin were measured under basal conditions, during fluid deprivation, 3% saline infusion, and water loading. Magnetic resonance images of the posterior pituitary also were obtained. In affected males, the effects of desmopressin therapy and linkage of the DI to markers for chromosome Xq28 were determined. In addition, the genes encoding vasopressin, aquaporin-2, the AVPR2 receptor, and its flanking regions were sequenced. This study showed that 4 males from 3 generations of the kindred have DI that is due to a deficiency of vasopressin, is corrected by standard doses of desmopressin, and segregates with markers for the AVPR2 gene in Xq28. However, no mutations were found in AVPR2 or its highly conserved flanking regions. Exome sequencing confirmed these findings and also revealed no deleterious variants in the provasopressin and aquaporin-2 genes. The 4 obligate female carriers osmo-regulated vasopressin in the low normal range. X-linked recessive transmission of DI can be due to a defect in either the secretion or the action of vasopressin. Other criteria are necessary to differentiate and manage the 2 disorders correctly.

Expanding the genetic landscape of oral-facial-digital syndrome with two novel genes.

Oral‐facial‐digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X‐linked dominant, X‐linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy‐spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.

Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?

The Ritscher-Schinzel syndrome (RTSCS) is a rare condition with craniofacial, cardiac and fossa posterior abnormalities. RTSCS is subdivided into Ritscher-Schinzel syndrome 1 (RTSCS1) caused by pathogenic variants in coiled-coil domain-containing protein 22 (CCDC22), and Ritscher-Schinzel syndrome 2 (RTSCS2) caused by pathogenic variants in WASH complex subunit 5 (WASHC5). CCDC22 is inherited in an X-linked recessive manner while WASHC5 is inherited in an autosomal recessive manner. Only 17 individuals with a molecular diagnosis are reported. In the past, the diagnosis of RTSCS was solely based on the clinical findings, and minimal diagnostic criteria has been proposed for the syndrome: Cardiac malformations (other than isolated patent ductus arteriosis), fossa posterior malformations, and certain dysmorphic features. However, those criteria are not present in all patients. We aim to further delineate the spectrum of CDCC22 associated RTSCS and present a novel patient with epileptic encephalopathy due to a presumed disease causing CCDC22 missense variant inherited from a healthy mother and grandmother. An affected maternal uncle had passed away at the age of 12 months and was thus unavailable for genetic testing. The proband and the maternal uncle had the typical facial dysmorphism associated with RTSCS, and they closely resembled previously published RTSCS2 patients with a molecular diagnosis. This suggests that RTSCS1 and RTSCS2 patients have a similar facial gestalt. We also review the literature on RTSCS, we explore potential differences and similarities between CCDC22 and W ASHC5 associated RTSCS and discuss the minimal diagnostic criteria.

ATP7A mutation with occipital horns and distal motor neuropathy: A continuum

ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489) (Kennerson et al., 2010). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein (Møller, 2015). Thus far OHS and SMAX3 only partially overlap. In fact patients with OHS usually have no distal motor neuropathy signs but, on the other hand, occipital horns, which are the main sign of OHS, have not been described in SMAX3 patient. We describe here a patient bearing a missense ATP7A mutation with associated signs of distal motor neuropathy as well as occipital horns, confirming that OHS and SMAX3 are a continuum.

Childhood Seeligmüller Strümpell Philip Disease: The First Case in Iraq and a Review of the Early Historic Documentation of the Disease in the Literature

Seeligmüller Strümpell Philip disease is characterized by familial progressive spastic paraplegia or paraparesis associated with a progressive deterioration of gait. The disorder is genetically heterogeneous and can be inherited in an autosomal dominant, autosomal recessive or X-linked recessive manner. The mode of inheritance involved has a direct impact on the chances of inheriting the disorder. The cornerstone of treatment is the use of various muscle relaxants. The disorder has not been reported or documented in Iraq. This paper aims to report the first case of childhood Seeligmüller Strümpell Philip disease in an Iraqi girl. Patients and Methods: A thirteen-year girl with childhood Seeligmüller Strümpell Philip disease who developed systemic lupus erythematosus is described and the early historic documentation of Seeligmüller Strümpell Philip disease in the medical literature is briefly updated. Results: The diagnosis of Seeligmüller Strümpell Philip disease in this girl was based on clinical findings and supported by electromyography and nerve conduction studies. Brain MRI showed normal findings. Few weeks before the patient was seen, they took her outside Iraq to Medipol Mega complex of Hospitals for treatment. They performed tenotomy and tenoplasty of the hip adductors, achilloplasty, and posterior capsule relaxation. When the girl was first seen at the Children Teaching Hospital of Baghdad Medical City, the parents regretted taking her outside Iraq for treatment as she didn’t show any improvement, and was still using the wheelchair. Conclusion: Unfortunately, the girl was seen too late, and despite consulting many doctors in Iraq and outside Iraq, she didn’t receive appropriate evidence based treatment and was treated unsatisfactorily surgically.

Miniature Pigs Carrying <i>DMD</i> Exon51 Deletion Suffered from Severe Myocardial Damage, Accelerated Muscle Atrophy and Malabsorption

Duchenne muscular dystrophy (DMD), inherited in an X-linked recessive manner, is a lethal disease affecting about 1/3600 males at birth. Mutations in the DMD gene have been shown to be the key determinant of the occurrence of DMD disease. Nowadays, removal of DMD exon 51 has been used as a common therapeutic intervention in disease animal models. Despite all these efforts, the clinical significance of DMD exon 51 has hardly been explored in large animals. Our study aimed to investigate the role of DMD exon 51 in the pathogenesis of DMD disease. We generated cell clones and miniature pigs lacking DMD exon 51 by CRISPR-Cas9 system. Significant changes in cell membrane integrity and apoptosis were found in genetically modified cell clones. All DMD pigs showed the accelerated pathological process of Duchenne muscular dystrophy. In addition, the ability of the small intestine of DMD pigs to digest and absorb nutrients was significantly reduced, compared to wild-type littermates. To conclude, this research could assist in our understanding of the pathological process of Duchenne muscular dystrophy. The findings of our investigation complemented those of earlier studies and might provide new insights into slow down the progression of this disease. Funding: This work was supported by grants from National Natural Science Foundation of China (No. 31572345 and 31472053), the Program for JLU Science and Technology Innovative Research Team (2017TD-28), the Fundamental Research Funds for the Central Universities, the Humanized IAPP gene preparation of human diabetes miniature swine model. Jilin Province Science and Technology Development Plan Project (No.20170623035TC) and the Program for Changjiang Scholars and Innovative Research Team in University in China (No. IRT16R32). Declaration of Interest: The authors declare no competing interest. Ethical Approval: All animal studies were approved by the Animal Welfare and Research Ethics Committee at Jilin University, and all procedures were conducted strictly in accordance with the Guide for the Care and Use of Laboratory Animals. All surgeries were performed under anesthesia, and every effort was made to minimize animal suffering.

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy.

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

Autosomal Recessive Hypohidrotic Ectodermal Dysplasia Caused by a Novel Mutation in EDAR Gene

Backgrounds: Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder, distinguished by hypotrichosis, hypohidrosis, and hypodontia. HDE can be inherited in X-linked recessive manner as a result of mutations in the ectodysplasin A (EDA) gene as well as autosomal dominant and autosomal recessive manners both of them caused by mutations in EDA receptor (EDAR) and EDAR-associated death domain (EDARADD) genes.Findings: In this report, we investigated a consanguineous Iranian family with autosomal recessive form of HED. A homozygous missense mutation was detected in exon 1 of EDAR gene in the proband (c.278C>G) resulting in p.C93S that alters the sequence of the EDAR protein. Conclusions: We facilitated the effective genetic counseling and prenatal diagnosis in this family through detection of the disease causing mutation.

Loss of Dystrobrevin Causes Muscle Degeneration and a Short Lifespan in Caenorhabditis elegans

Duchene’s muscular dystrophy (DMD) is an inherited disorder in an X-linked recessive manner. Lack of dystrophin causes progressive muscle degeneration. Dystrophin structurally connects to actin filaments at the N-terminus while the C-terminus interacts with an integral domain of the dystroglycan complex. Among the associated molecules, dystrobrevin acts as a modulator protein exerting dystrophin's function for strengthening the cell stability. Previous data has reported the delayed muscle degeneration following an overexpression of the dystrobrevin (dyb) gene in the DMD-phenotype C. elegans, whose dystrophin (dys) gene was missing. This finding indicates the role of a modulator protein, rather than dystrophin, to maintain the cell integrity. The present study aims to investigate the phenotypes of C. elegans, due to dyb- or dys-deficiency. When compared with the wild-type, the dyb-deficient worms exhibited uncoordinated locomotion and lysis of the muscular layer in the body wall and internal organs as well as those observed in the dys-deficient worms. The ultrastructure of both mutant worms appeared severe muscle degeneration, decrease of the mitochondria, and replacement of fibrotic tissue, particularly the dys-mutant which was even more severe. Additionally, a shorter lifespan was observed with a 17 % reduction (p < 0.05) in dyb-deficient worms and 27 % reduction (p < 0.05) in dys-deficient worms when compared to wild-type. It is speculated that dystrobrevin may stabilize the cell through interaction with other protein complexes at the plasma membrane while it also binds to dystrophin. Therefore, the loss of dystrobrevin is also sufficient to disrupt the signaling pathway and causes muscle degeneration.

Genetic testing for color vision deficiency

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for color vision deficiency (CVD). Deuteranopia affects 1 in 12 males and is inherited in an X-linked recessive manner. It is associated with variations in the OPN1LW (OMIM gene: 300822; OMIM disease: 303900) and OPN1MW (OMIM gene: 300821; OMIM disease: 303800) genes. Tritanopia has a prevalence of 1 in 10 000, is inherited in an autosomal dominant manner, and is related to variations in the OPN1SW (OMIM gene: 613522; OMIM disease: 190900) gene. Blue cone monochromatism has a prevalence of 1 in 100 000, is inherited in an X-linked recessive manner and is related to mutations in the OPN1LW (OMIM gene: 300822; OMIM disease: 303700) and OPN1MW (OMIM gene: 300821; OMIM disease: 303700) genes. Clinical diagnosis is based on clinical findings, ophthalmogical examination, family history, electroretingraphy, color vision testing and dark adaptometry. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.