X-linked Inheritance Pattern Research Articles

Cohesin complex-associated holoprosencephaly.

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

Identification of a missense variant in CLDN2 in obstructive azoospermia.

Obstructive azoospermia (OA), defined as an obstruction in any region of the male genital tract, accounts for 40% of all azoospermia cases. Of all OA cases, ~30% are thought to have a genetic origin, however, hitherto, the underlying genetic etiology of the majority of these cases remain unknown. To address this, we took a family-based whole-exome sequencing approach to identify causal variants of OA in a multiplex family with epidydimal obstruction. A novel gain-of-function missense variant in CLDN2 (c.481G>C; p.Gly161Arg) was found to co-segregate with the phenotype, consistent with the X-linked inheritance pattern observed in the pedigree. To assess the pathogenicity of this variant, the wild and mutant protein structures were modeled and their potential for strand formation in multimeric form was assessed and compared. The results showed that dimeric and tetrameric arrangements of Claudin-2 were not only reduced, but were also significantly altered by this single residue change. We, therefore, envisage that this amino acid change likely forms a polymeric discontinuous strand, which may lead to the disruption of tight junctions among epithelial cells. This missense variant is thus likely to be responsible for the disruption of the blood-epididymis barrier, causing dislodged epithelial cells to clog the genital tract, hence causing OA. This study not only sheds light on the underlying pathobiology of OA, but also provides a basis for more efficient diagnosis in the clinical setting.

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders

BackgroundRecently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders. MethodsGenomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM). ResultsThirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1. ConclusionA diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.

011–X-Linked Hypophosphatemia (XLH): New Knowledge for Nurses Regarding Genetics, Pathophysiology and Clinical Presentation

Background: Over 80 years ago Fuller Albright reported a vitamin D-resistant form of rickets, which is likely the initial description of X-linked hypophosphatemia (XLH). Recently the genetic basis of the disease has been identified and a more complete understanding of the pathophysiology has emerged. Purpose: To increase awareness of the latest published data on the genetics, clinical manifestations, differential diagnoses, biochemical findings, as well as growth and development of patients with XLH. Description of Topic: XLH is a rare, progressive, life-long disorder and the most common form of heritable rickets. The estimated prevalence of XLH is 1:20,000 to 1:25,000. XLH is caused by loss-of-function mutations in the phosphate regulating endopeptidases on the X-chromosome (PHEX) gene, leading to high circulating levels of fibroblast growth factor 23 (FGF23). Over 300 PHEX mutations have been reported. An X-linked dominant inheritance pattern is typical; however, de novo PHEX mutations are reported in up to 20-30% of the cases. Excess FGF23 increases urinary phosphate losses with consequent hypophosphatemia, resulting in rickets and osteomalacia. Clinical manifestations may include lower limb deformities, short stature, bone and joint pain, dental abscesses, delayed walking, and gait abnormalities. Neurological features may include Chiari 1 malformation and craniosynostosis. Low serum phosphate levels, a low renal tubular threshold for phosphate reabsorption (TmP/GFR), and low or normal circulating 1,25(OH)2D are characteristic biochemical findings in patients with XLH. The symptoms of XLH vary among individuals and while there is similar pathophysiology for children and adults, clinical manifestations can differ. Debilitating consequences in adults include osteoarthritis, enthesopathy, spinal stenosis and pseudofractures. In addition, complications of conventional medical therapy (phosphate salts and active vitamin D analogs) include nephrocalcinosis and hyperparathyroidism. Clinical Implications: Previously, XLH was considered a disorder that manifests only during growth; however, adolescent patients require attention along with a smooth transition to adult care. In addition, recognition of the complex disease features of XLH is essential for accurate diagnosis and management. Pediatric endocrine nurses are well qualified to provide the latest disease state education to patients and families, and to encourage routine clinical evaluation to assess treatment response, disease progression, and therapeutic complications.

A novel frameshift mutation in FRMD7 causes X-linked infantile nystagmus in a Chinese family

BackgroundInfantile nystagmus (IN) is an oculomotor disorder that is characterized by conjugate involuntary, rapid and repetitive movement of the eyes. To date, the pathogenesis of IN remains unclear. Many patients show an X-linked inheritance pattern. In this study, we explored the mutation in the FERM domain-containing 7 (FRMD7) gene in a Chinese family with X-linked infantile nystagmus.MethodsWe conducted comprehensive ocular examinations and collected 5 ml of blood samples from members of a family with X-linked IN and 100 normal controls. Mutations in FRMD7 were identified by sequencing PCR products.ResultsWe found a 7-bp deletion(c.823-829delACCCTAC) in the 9th exon of FRMD7 in a Chinese family with IN, which predicted a truncation of the protein.ConclusionsThis study reported a novel mutation of the FRMD7 gene occurred in a Chinese family with IN, thus expanding the spectrum of FRMD7 mutations causing IN, and further confirming that the mutations of FRMD7 are the underlying molecular cause of IN.

Hemophilia

<h3>ABSTRACT</h3> Hemophilia is a rare, congenital bleeding disease with an X-linked recessive inheritance pattern. It is characterized by absent, decreased, or dysfunctional coagulation factor VIII (FVIII) or factor IX (FIX). Individuals with severe hemophilia bleed into the joints, soft tissue, and muscles, which can be debilitating. Although hemophilia is a serious life-long bleeding disease, understanding the pathogenesis of the disease leads to better patient treatment and improved patient outcomes.

Clinical Severity Correlates with in Vitro Residual Function of FANCB Missense Variants

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome, characterized by congenital anomalies, bone marrow failure and cancer predisposition. FA patients with mutations in FANCB exhibit X-linked inheritance pattern. FANCB patients have been frequently associated with a severe phenotype, resembling VACTERL association with hydrocephalus, although heterogeneity in these patients still exists and is not well understood. To determine the underlying pathogenesis of clinical heterogeneity, we investigated phenotype-genotype correlations in 19 patients from 16 families with FANCB pathogenic variants. We also investigated functional properties of five FANCB missense variants to determine their possible contribution to clinical manifestations.Patients were accrued at the Rockefeller University Hospital in the International Fanconi Anemia Registry. Among the 16 families with FANCB pathogenic variants, three carry nonsense variants, five have indels, two with large deletions, one has an intragenic duplication, two with canonical splice site variants that should result in aberrant splicing, and five display missense variants. One patient carried both an indel and a missense variant. Patients with variants leading to FANCB truncations (including nonsense variants, indels, large deletions/duplications, and splice variants) tend to show shorter survival and earlier hematologic onset, than patients with missense variants. However, the differences did not reach statistical significance due to small sample size.Functional properties of five missense variants were examined by overexpression of variant cDNA (HA-tagged) in FANCB-null fibroblasts, followed by assessment of FANCD2 ubiquitination, mitomycin C (MMC) sensitivity, FANCD2 foci formation and HA-FANCB localization. We found that expression of p.W479G and p.L676P FANCB variants leads to near-normal FANCD2 ubiquitination upon MMC exposure, and MMC sensitivity. Conversely, p.L43S-expressing cells behaved like FANCB-null fibroblasts. Expression of p.L329P and p.G750V resulted in low levels of FANCD2 ubiquitination upon MMC exposure and intermediate MMC sensitivity. Expression of p.L43S resulted in smaller-sized and lowest quantity of FANCD2 foci with predominant cytoplasmic localization of HA-FANCB, while other variants showed intermediate phenotype. We quantified the nuclear expression of HA-FANCB, which confirmed the lowest relative nuclear expression of p.L43S variant, suggesting a defect in nuclear localization necessary for the interstrand crosslink repair. We also assessed splicing defects in the patient primary cells by reverse transcription PCR. Majority of the transcripts in the patient carrying c.1435T>G (predicted to express p.W479G) variant showed aberrant splicing, exon 7 skipping, which should result in an out-of-frame truncated protein. Although the expression level of c.1435T>G encoding the missense variant p.W479G is lower than the splicing variant, its functional characteristics were near-normal, thus reflecting relatively milder phenotype in this patient. Overall patient survival correlated with residual function of their FANCB variants as assessed by in vitro assays described above.In summary, we report clinical course and mutation types of 19 patients with FANCB pathogenic variants. We also report that FANCB missense variants can have varying degree of residual function, which correlates with patient survival. Our data suggest that variant-level analysis may be a useful prognostic marker of patient outcome. In vitro assays evaluating the residual function of proteins with missense variants may help to predict patient outcome. DisclosuresNo relevant conflicts of interest to declare.

Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature

BackgroundAutosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity.MethodsThis study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia.ResultsUsing whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2).ConclusionsThis study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.

A Case of Familial Focal Dermal Hypoplasia: A Report of 3 Cases in Consecutive Generations

Focal dermal hypoplasia (FDH), or Goltz syndrome, is a rare multisystem disorder affecting mesodermal and ectodermal structures, with the skin, eyes, teeth, and musculoskeletal systems most commonly affected. FDH results from mutations in the PORCN gene. Ninety-five percent of cases arise from novo mutations, whereas 5% are hereditary with an X-linked dominant inheritance pattern. Here, we describe an uncommon presentation of FDH in three consecutive generations. Patient 1 is an 8-month-old female born of non-consanguineous marriage who presented with diffuse alopecia of the scalp, linear hypopigmented, atrophic papules, and plaques with peripheral hyperpigmentation on the left hemiabdomen and right lateral leg along Blaschko's lines as well as syndactyly of the right second and third toes. Skin biopsy from the abdomen showed a thin epidermis with flattened rete ridges and massive dermal edema within collagen fibers and reactive capillaries. Family history was significant for similar skin lesions and bone deformities in her mother and similar skin lesions in her grandmother. Patient 2 (patient 1’s mother) is a 17-year-old female with similar linear hypopigmented, atrophic plaques with peripheral hyperpigmentation on the abdomen and right axilla, syndactyly of the right hand, patchy alopecia of the scalp, microdontia, teeth fusion, enamel defects, verrucous papillomas in the axillae and onycholysis. Patient 3 (patient 1’s grandmother), presented with similar hypopigmented, atrophic plaques on the abdomen and left arm.

Four-Generation Pedigree of Monozygotic Female Twins Reveals Genetic Factors in Twinning Process by Whole-Genome Sequencing.

Familial monozygotic (MZ) twinning reports are rare around the world, and we report a four-generation pedigree with seven recorded pairs of female MZ twins. Whole-genome sequencing of seven family members was performed to explore the featured genetic factors in MZ twins. For variations specific to MZ twins, five novel variants were observed in the X chromosome. These candidates were used to explain the seemingly X-linked dominant inheritance pattern, and only one variant was exonic, located at the 5'UTR region of ZCCHC12 (chrX: 117958597, G > A). Besides, consistent mitochondrial DNA composition in the maternal linage precluded roles of mitochondria for this trait. In this pedigree, autosomes also contain diverse variations specific to MZ twins. Pathway analysis revealed a significant enrichment of genes carrying novel SNVs in the epithelial adherens junction-signaling pathway (p = .011), contributed by FGFR1, TUBB6, and MYH7B. Meanwhile, TBC1D22A, TRIOBP, and TUBB6, also carrying similar SNVs, were involved in the GTPase family-mediated signal pathway. Furthermore, gene-set enrichment analysis for 533 genes covered by copy number variations specific to MZ twins illustrated that the tight junction-signaling pathway was significantly enriched (p < .001). Therefore, the novel changes in the X chromosome and the provided candidate variants across autosomes may be responsible for MZ twinning, giving clues to increase our understanding about the underlying mechanism.

Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report

BackgroundDyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene.Case presentationHerein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail dystrophy, leukoplakia of the tongue, premature graying of hair, watery eyes and dental caries. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of disease condition. Pedigree analysis suggested a possible X-linked pattern of inheritance. Genetic testing in the proband showed a novel hemizygous, non-synonymous likely pathogenic variant [NM_001363.4: c.1054A > G: p.Thr352Ala] in the PUA domain of the DKC1 gene. Quantitative polymerase chain reaction for relative telomere length measurements performed in the proband showed that he had very short telomeres [0.38, compared to a control median of 0.71 (range 0.44–1.19)], which is consistent with the DC diagnosis. Co-segregation analysis of the novel mutation and telomere length measurements in the extended family members could not be performed as they were unwilling to provide consent for testing.ConclusionsThe novel variant detected in the DKC1 gene adds further to the existing scientific literature on the genotype-phenotype correlation of DC, and has important implications for the clinical and molecular characterization of the disease.

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study

Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12–2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75–4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc.

Hereditary Disorders in Circassians of the Karachay-Cherkess Republic

The paper aims to review the diversity of monogenic hereditary disorders (MHD) in the Circassians of the Karachay-Cherkess Republic (KCR). In total, 50817 Circassians were investigated. The populations of eight districts (Ust-Dzhegutinsky, Karachayevsky, Malokarachayevsky, Prikubansky, Khabezsky, Abazinsky, Nogaysky, and Adyge-Khablsky) and of the city of Cherkessk were studied. Two hundred fifty patients from 167 families were registered. The prevalence of MHD in Circassians happens to be 1: 214. The nosological spectrum of MHD in Circassians includes 70 disorders: 34 with autosomal dominant, 25 with autosomal recessive, and 11 with X-linked inheritance patterns. Confirmatory DNA diagnostics was performed in 56 patients. Accumulation of particular diseases in the Circassian population was revealed in comparison with the previously surveyed ethnic groups/populations of Russia. The cluster analysis was performed on the basis of the prevalence of AD and AR disorders and determined the genogeographic position of the Circassians among eight ethnic groups of Russia (13 populations in total). The total size of the surveyed populations was over 3.5 million people: six Russian regions, Tatars of the Tatarstan, Bashkirs of the Bashkortostan, Chuvashs of the Chuvash Republic, Maris of the Mari El Republic, Udmurts of the Udmurt Republic, Adygeans of the Republic of Adygea, and Circassians of the Karachay-Cherkess Republic. The general pattern for AD and AR diseases was similar: six Russian populations group within a single cluster, being remote from people of the Volga-Ural region and the North Caucasus (Adyghe: Adygeans and Circassians).

Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy

X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy.

Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features.

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.

Whole genome sequencing identifies etiology of recurrent male intrauterine fetal death.

To identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males. Whole genome sequencing was performed on DNA from five healthy obligatory carrier females and an unaffected male offspring of a multigenerational pedigree with recurrent second-trimester IUFD of males (n=19). When documented, all deaths occurred at ≤20weeks of gestation. Hydrops fetalis was diagnosed at death in the most recent case. Following variant filtering based on a recessive X-linked inheritance pattern, a rare FOXP3 frameshift mutation (p.D303fs*87) that results in a premature truncation of the protein was discovered. Sanger sequencing confirmed the mutation in the affected fetus. The FOXP3 gene encodes for a transcriptional regulator critical to the function of regulatory T cells. FOXP3 mutations are associated with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome which exclusively affects males and may present with a potentially life-threatening complex autoimmune disorder in early childhood. Here, we demonstrate the utility of whole genome sequencing-based pedigree analysis to identify the genetic cause for recurrent IUFD when chromosome studies, including microarray analysis, are normal. Further studies are needed to determine the prevalence of FOXP3-mediated IUFD in males. © 2017 John Wiley & Sons, Ltd.

An X‐linked Myh11‐CreERT2 mouse line resulting from Y to X chromosome‐translocation of the Cre allele

The Myh11-CreERT2 mouse line (Cre+ ) has gained increasing application because of its high lineage specificity relative to other Cre drivers targeting smooth muscle cells (SMCs). This Cre allele, however, was initially inserted into the Y chromosome (X/YCre+ ), which excluded its application in female mice. Our group established a Cre+ colony from male ancestors. Surprisingly, genotype screening identified female carriers that stably transmitted the Cre allele to the following generations. Crossbreeding experiments revealed a pattern of X-linked inheritance for the transgene (k > 1000), indicating that these female carries acquired the Cre allele through a mechanism of Y to X chromosome translocation. Further characterization demonstrated that in hemizygous X/XCre+ mice Cre activity was restricted to a subset arterial SMCs, with Cre expression in arteries decreased by 50% compared to X/YCre+ mice. This mosaicism, however, diminished in homozygous XCre+ /XCre+ mice. In a model of aortic aneurysm induced by a SMC-specific Tgfbr1 deletion, the homozygous XCre+ /XCre+ Cre driver unmasked the aortic phenotype that is otherwise subclinical when driven by the hemizygous X/XCre+ Cre line. In conclusion, the Cre allele carried by this female mouse line is located on the X chromosome and subjected to X-inactivation. The homozygous XCre+ /XCre+ mice produce uniform Cre activity in arterial SMCs.

Forensic efficiency parameters of the Investigator Argus X-12 kit in women from two Mestizo and seven Amerindian populations from Mexico

Allele frequency distribution and statistical parameters of forensic efficiency concerning the Investigator Argus X-12 kit (Qiagen, Hilden, Germany) were determined in a total sample of 641 unrelated Mexican females, including two Mestizo-admixed- populations (n=309) and seven Amerindian groups (n=332) from the main regions of the country. Most of the 12 X-STRs were in agreement with Hardy-Weinberg expectations in all nine Mexican populations. The power of discrimination in females (PD) and Median exclusion chance for trios (MECT) and duos (MECD) of this genetic system based on X-STRs were >99.99%. Although Mexican populations showed significant pairwise differentiation, a closer relationship was evident between Amerindian groups and nearby Mestizos, in agreement with historical records, previous genetic studies, and X-linked inheritance pattern expectations.

Hemophilia A and Induced Pluripotent Stem Cells

Hemophilia A is a hemorrhage disorder inherited according to the X-linked inheritance pattern. It affects about 1 in 4,000 to 10,000 males. Permanent changes in the F8 gene result in hemophilia A. These changes result in an abnormal version of coagulation factor VIII. This abnormal condition determines the kinds of the disorder, namely, severe and mild or moderate hemophilia A. Currently, to treat hemophilia A, infusions of plasma-derived or recombinant factor VIII can be used. However, the cost is extremely high. It makes heavy burdens on the patients, their families or the health care system. Therefore, advanced therapy as iPSCs technique has attracted attention of researchers to research for curing this disorder. For example, to obtain edited DNA segments due to hemophilia A, this technique can be used. Research results in animal models have shown important advances.