91 research outputs found
Fryns syndrome associated with recessive mutations in PIGN in two separate families
No full textFryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.Aideen M. McInerney-Leo, Jessica E. Harris, Michael Gattas, Elizabeth E. Peach, Stephen Sinnott, Tracy Dudding-Byth, Sulekha Rajagopalan, Christopher P. Barnett, Lisa K. Anderson, Lawrie Wheeler, Matthew A. Brown, Paul J. Leo, Carol Wicking and Emma L. Dunca
A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A
No full textBACKGROUND: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy. PATIENTS AND METHODS: We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation. RESULTS: Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C>T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100,000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals. CONCLUSIONS: The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.Mark A Corbett, Tracy Dudding-Byth, Patricia A Crock, Elena Botta ... Joanna Crawford ... Jozef Gécz ... et al
IQSEC2 mutation update and review of the female‐specific phenotype spectrum including intellectual disability and epilepsy
No full textThe IQSEC2‐ related disorders represent a spectrum of X‐chromosome phenotypes with intellectual disability (ID) as the cardinal feature. Here, we review the increasing number of reported families and isolated cases have been reported with a variety of different pathogenic variants. The spectrum of clinical features is expanding with early‐onset seizures as a frequent comorbidity in both affected male and female patients. There is a growing number of female patients with de novo loss‐of‐function variants in IQSEC2 have a more severe phenotype than the heterozygous state would predict, particularly if IQSEC2 is thought to escape X‐inactivation. Interestingly, these findings highlight that the classical understanding of X‐linked inheritance does not readily explain the emergence of these affected females, warranting further investigations into the underlying mechanisms
Different types of disease-causing non-coding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability
No full textThe pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that non-coding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different non-coding variants. We used comprehensive structural, single nucleotide and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, RT-PCRs, western blots and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic non-coding variants: a retrotransposon insertion, a novel intronic splice donor and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favour of a regulatory non-coding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic non-coding variant discovery.Michael J. Field, Raman Kumar, Anna Hackett, Sayaka Kayumi, Cheryl A. Shoubridge, Lisa J. Ewans, Atma M. Ivancevic, Tracy Dudding, Byth, Renée Carroll, Thessa Kroes, Alison E. Gardner, Patricia Sullivan, Thuong T. Ha, Charles E. Schwartz, Mark J. Cowley, Marcel E. Dinger, Elizabeth E. Palmer, Louise Christie, Marie Shaw, Tony Roscioli, Jozef Gecz, Mark A. Corbet
Fryns syndrome associated with recessive mutations in PIGN in two separate families
No full textFryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in <i>PIGN</i> were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in <i>PIGN</i> (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for <i>PIGN</i> mutations. Mutations in <i>PIGN</i> have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in <i>PIGN</i>. Whether <i>PIGN</i> affects other syndromic and non-syndromic forms of CDH warrants investigation
‐related encephalopathy in males due to missense variants in the pleckstrin homology domain
No full textPathogenic variants in IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause a variety of neurodevelopmental disorders, with intellectual disability as a uniform feature. We report five cases, each with a novel missense variant in the pleckstrin homology (PH) domain of the IQSEC2 protein. Male patients all present with moderate to profound intellectual disability, significant delays or absent language and speech and variable seizures. We describe the phenotypic spectrum associated with missense variants in PH domain of IQSEC2, further delineating the genotype–phenotype correlation for this X‐linked gene
Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery
No full textData source: Supporting information, https://doi.org/10.1002/humu.23557
Link to a related website: http://diposit.ub.edu/dspace/bitstream/2445/163797/1/689247.pdf, Open Access via UnpaywallHighly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally-inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans. This article is protected by copyright. All rights reserved.Raman Kumar, Alison Gardner, Claire C. Homan, Evelyn Douglas, Heather Mefford, Dagmar Wieczorek, Hermann-Josef Lüdecke, Zornitza Stark, Simon Sadedin, The Broad CMG, Catherine Bearce Nowak, Jessica Douglas, Gretchen Parsons, Paul Mark, Lourdes Loidi, Gail E. Herman, Theresa Mihalic Mosher, Meredith K. Gillespie, Lauren Brady, Mark Tarnopolsky, Irene Madrigal, Jesús Eiris, Laura Domènech Salgado, Raquel Rabionet, Tim M. Strom, Naoko Ishihara, Hidehito Inagaki, Hiroki Kurahashi, Tracy Dudding-Byth, Elizabeth E. Palmer, Michael Field, Jozef Gec
Factor V Leiden and adverse pregnancy outcome
No full textIntrauterine fetal death, fetal growth restriction (FGR) and pre-eclampsia are major causes of fetal and maternal morbidity and mortality; and placental insufficiency is frequently proposed as the most important underlying mechanism. Given the importance of establishing and maintaining an adequate placental circulation, hereditary thrombophilias are postulated as a possible cause of placental insufficiency. Despite initial reports supporting an association between factor V Leiden (fVL) and adverse pregnancy outcomes, a number of other studies yielded conflicting results. A systematic review and meta-analysis of the literature up to January 2003 was undertaken to address the question of whether the common maternal fVL genotype is associated with an increased risk of adverse pregnancy outcomes (pre-eclampsia, fetal growth restriction and fetal loss). Subsequent meta-analyses were also evaluated. To address the shortfalls observed in the large number of small and possibility underpowered case-control studies, a decision was made to undertake a large nested case-control study within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. The aim of this study was to evaluate the association between: 1) maternal fVL and intrauterine fetal death, fetal growth restriction and pre-eclampsia; 2) fetal fVL and intrauterine fetal death, fetal growth restriction; 3) maternal prothrombin gene variant (PGV) and intrauterine fetal death, fetal growth restriction and pre-eclampsia and 4) fetal PGV and intrauterine fetal death, fetal growth restriction and pre-eclampsia. Data from other published cohort studies was combined by meta-analysis to increase the power of detecting an association. Overall, the results of the study within the large ALSPAC cohort show no statistically significant association between maternal/fetal fVL or PGV, either alone or in combination with birth weight <10th centile. Furthermore, the FGR meta-analysis which pooled the results of this cohort study and other cohort studies found no evidence of an effect of maternal fVL on FGR. Given the size of the pooled sample, there was 80% power to detect an OR of 1.09, indicating that if an effect of fVL on FGR was missed by this meta-analysis, it would be quite small. The results of this study within the large ALSPAC cohort show no statistically significant association between maternal or fetal fVL or PGV, either alone or in combination with pre-eclampsia. However, increasing the power by combining this study with other cohort studies by meta-analysis revealed a positive association between maternal fVL and pre-eclampsia with an OR of 1.49 (95% CI 1.13-1.96 p=0.003). A narrative review was subsequently published examining the translation from statistical association to change in clinical practice with respect to fVL and adverse pregnancy outcomes. The thesis concludes with a discussion of management in different clinical scenarios relating to fVL and adverse pregnancy outcomes, and the identification of future priority research areas
Atypical Angelman syndrome with macrocephaly due to a familial imprinting center deletion
No full textCarbimazole/methimazole embryopathy in siblings: a possible genetic susceptibility
No full textBACKGROUND: The teratogenic effects of antenatal exposure of antithyroid drugs, carbimazole and methimazole have been well reported in the literature. These comprise of typical facial features and a wide variety of malformations such as choanal atresia, tracheo-esophageal anomalies, congenital heart disease and ectodermal defects. However, the longitudinal studies have failed to establish the consistent teratogenicity of these drugs. CASES: We report here two siblings with physical features consistent with carbimazole/methimazole embryopathy. We also describe previously unreported minor dental anomalies in these siblings with antenatal exposure of carbimazole. CONCLUSION: Generally, only a small proportion of prenatally exposed children have the typical manifestations, and the presence in siblings supports a possible hereditary susceptibility to carbimazole/ methimazole embryopathy. This highlights the importance of recognizing this diagnosis before a subsequent pregnancy
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