Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders

Morleo, Manuela; Franco, Brunella

doi:10.1136/jmg.2008.058305

Cited by 57 publications

(65 citation statements)

References 50 publications

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“…A non-X-linked cause of AS has been suggested previously, partly due to a lack of nonrandom X chromosome inactivation, which would be expected in a disorder with an X-linked genetic defect [Wang et al, 2009]. However, this is not always present in X-linked disorders, such as e.g., Rett syndrome [Ropers et al, 1982;Yilmaz et al, 2007;Morleo and Franco, 2008]. Furthermore, a causal mutation in an autosomal gene with a sex-limited effect that causes AS in females has also been suggested [Prontera et al, 2013].…”

Section: Discussionmentioning

confidence: 95%

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Lund¹,

Striano

Sorte

et al. 2016

Mol Syndromol

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Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.

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Section: Discussionmentioning

confidence: 95%

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Lund¹,

Striano

Sorte

et al. 2016

Mol Syndromol

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“…It has been proposed that the pattern of XCI, not only in blood cells but also in other tissues influences the development of clinical features in female patients with an X-linked male lethal disorder resulting in a high phenotypic variability (from the most severe phenotype to a milder manifestation or the total absence of clinical features). 19 Similarly, the phenotype also varies in female patients with a microdeletion including PORCN (as well as SLCA38A5 and FTSJ1) and skewed XCI. Typical clinical features of FDH, such as linear skin lesions, dermal hypoplasia, nail dystrophy, and asymmetric bone defects, but no ocular abnormalities have been observed in five sporadic female patients with a submicroscopic deletion encompassing PORCN and additional genes.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of the X chromosome inactivation (XCI) status using the androgen receptor assay revealed severely skewed XCI in all four patients with a pattern ranging from 96:4 to 100:0 (K. Kutsche, unpublished data) that is in line with extensive XCI skewing in patients with MLS and HCCS mutation. 10,19 Ethical approval for this study was obtained and informed consent for the genetic analyses was received from parents or their legal guardians.…”

Section: Subjectsmentioning

confidence: 99%

Goltz–Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap

et al. 2009

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Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

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“…These results were hypothesized to be explained by the observation that most genes escaping XCI are not fully expressed from the Xi, demonstrating that escape from inactivation is generally partial and incomplete. It was speculated that a threshold level of transcription of OFD1 was required by cells during embryogenesis, explaining the male lethality observed in the total absence of OFD1 protein [Morleo and Franco, 2008]. Thus the severe cerebral and renal phenotype could be explained by the presence of complete skewed X inactivation in all analyzed fetal tissues.…”

Section: To the Editormentioning

confidence: 98%

Cerebral dysgenesis does not exclude OFD I syndrome

Thauvin‐Robinet

Lesca

Aral

et al. 2011

American J of Med Genetics Pt A

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In 2006 Lesca et al. described an oral-facial-digital (OFD) syndrome with cerebellar dysgenesis in a sporadic malformative female fetus presenting with disproportionally large head with short limbs, hypertelorism, broad nasal root, long philtrum, severe micrognathia, microstomia, cleft palate, large tri-lobulated tongue, lingual hamartoma, hypertrophic frenulae, short upper limbs with brachydactyly, polysyndactylies of the feet and hands. She also had cerebral dysgenesis involving all the brain structures including midline structures. Neuropathological examination showed a severe disturbance of the architecture of both hemispheres, more severe on the right side, with four cystic structures suggesting arachnoidal cysts located between the hemispheres. Olfactory stalks, mammillary bodies, anterior and hippocampal commissures, septum pellucidum, and corpus callosum were absent. Cerebellum and brainstem were hypoplastic: the small cerebellar hemispheres were abnormally smooth with poorly developed lobules and folia; the vermis displayed a posterior agenesis. On the right hemisphere as on most part of the left one, microscopic findings displayed a complete disruption of the developing mantle with severe disturbance of the neural migration and neural differentiation. Because of the association of dysmorphic features, cleft palate, lobulate tongue, lingual hamartoma, hypertrophic frenula, and polysyndactylies of the feet and hands, the fetus fulfilled the diagnosis of OFD syndrome. The cerebral involvement would make it closer to OFD type VI, but brain malformations appeared far more severe, with complex and generalized cortical dysgenesis, evoking a disturbance occurring at a very early stage of the embryogenesis. The full coding sequence of the GLI3 gene (OMIM 165240) was screened to exclude an unusual form of Pallister-Hall syndrome (OMIM 146510) and appeared normal. Most likely, an autosomal recessive mode of inheritance was considered. At that time, the authors estimated that sequencing of the OFD1 gene was not appropriate due to the severity of the cerebral malformations.

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Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders

Cited by 57 publications

References 50 publications

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Goltz–Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap

Cerebral dysgenesis does not exclude OFD I syndrome

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