X‐inactivation and marker studies in three families with incontinentia pigmenti: implications for counselling and gene localisation

Woffendin, Hayley; Jakins, T.; Jouet, Monique; Stewart, Helen; Landy, Sarah; Haan, Eric; Harris, Ann; Read, Andrew P.; Kenwrick, Sue

doi:10.1034/j.1399-0004.1999.550110.x

Cited by 15 publications

(6 citation statements)

References 11 publications

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“…Hence, the female can present with the full blown phenotype that is also seen in males carrying a mutation in that gene [Frints et al., ; Hagens et al., ]. Second, cells with the mutation are only viable in case of extreme (but not complete) secondary skewing against this mutation with the prime example of incontinentia pigmenti (MIM# 308300) [Woffendin et al., ]. Third, a mutation causing ID can be accompanied by skewing that had occurred by chance.…”

Section: Discussionmentioning

confidence: 99%

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

et al. 2016

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Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males due to the hemizygous state of their X chromosome. Carrier females are generally unaffected due to the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analysed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; p=0.029). Whole exome sequencing of 19 females with extreme skewing revealed causal variants in 6 females in the XLID genes DDX3X, NHS, WDR45, MECP2 and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in 3 of these patients. Moreover, variants likely accounting for skewing only, were detected in MED12, HDAC8 and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.

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Section: Discussionmentioning

confidence: 99%

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

et al. 2016

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“…gether with the skin-pigmentation abnormality, constitute the typical IP phenotype. The IP gene is thought to be essential for viability, since affected hemizygous male individuals die in utero and female patients survive with the mutant X chromosome selectively inactivated (Parrish et al 1996;Woffendin et al 1999). On the basis of these characteristics, we screened a gene called "NEMO" and identified mutations in multiple IP patients (International IP Consortium 2000).…”

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confidence: 99%

Atypical Forms of Incontinentia Pigmenti in Male Individuals Result from Mutations of a Cytosine Tract in Exon 10 of NEMO (IKK-γ)

Aradhya

Courtois

Rajkovic

et al. 2001

The American Journal of Human Genetics

139

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Familial incontinentia pigmenti (IP [MIM 308310]), or Bloch-Sulzberger syndrome, is an X-linked dominant and male-lethal disorder. We recently demonstrated that mutations in NEMO (IKK-gamma), which encodes a critical component of the NF-kappaB signaling pathway, were responsible for IP. Virtually all mutations eliminate the production of NEMO, causing the typical skewing of X inactivation in female individuals and lethality in male individuals, possibly through enhanced sensitivity to apoptosis. Most mutations also give rise to classic signs of IP, but, in this report, we describe two mutations in families with atypical phenotypes. Remarkably, each family included a male individual with unusual signs, including postnatal survival and either immune dysfunction or hematopoietic disturbance. We found two duplication mutations in these families, at a cytosine tract in exon 10 of NEMO, both of which remove the zinc (Zn) finger at the C-terminus of the protein. Two deletion mutations were also identified in the same tract in additional families. However, only the duplication mutations allowed male individuals to survive, and affected female individuals with duplication mutations demonstrated random or slight skewing of X inactivation. Similarly, NF-kappaB activation was diminished in the presence of duplication mutations and was completely absent in cells with deletion mutations. These results strongly indicate that male individuals can also suffer from IP caused by NEMO mutations, and we therefore urge a reevaluation of the diagnostic criteria.

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“…Since IP is an X‐linked dominant disorder, it affects predominately females. Genetic analysis has indicated Xq28 to be the major locus for familial IP (4). It has recently been shown that most cases of IP are due to mutations in the gene for NEMO (NF‐kappaB essential modulator)/IKKgamma (IkappaB kinase‐gamma).…”

Section: Discussionmentioning

confidence: 99%

Incontinentia Pigmenti Presenting as Seizures

Hubert

Callen

2002

Pediatric Dermatology

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Incontinentia pigmenti is a rare disorder that may affect many systems including the skin, central nervous system, bone, and eyes. We describe a 13-day-old girl who developed seizures on day 1 of life and was placed on antiseizure medication. On approximately day 4 of life, she developed a vesicular rash on her trunk and extremities. The pediatric team prescribed intravenous acyclovir and diphenhydramine cream. These were used without improvement. At dermatology consultation, linear and swirled vesicular lesions were seen. A skin biopsy specimen revealed eosinophils within intraepidermal vesicles consistent with a diagnoses of incontinentia pigmenti. This case of incontinentia pigmenti is of interest in that the initial symptom was a seizure disorder.

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X‐inactivation and marker studies in three families with incontinentia pigmenti: implications for counselling and gene localisation

Cited by 15 publications

References 11 publications

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

Atypical Forms of Incontinentia Pigmenti in Male Individuals Result from Mutations of a Cytosine Tract in Exon 10 of NEMO (IKK-γ)

Incontinentia Pigmenti Presenting as Seizures

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