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FLNA genomic rearrangements cause periventricular nodular heterotopia.

ABSTRACT: To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNA sequencing is negative.Screening of 35 patients from 33 pedigrees on an Affymetrix 6.0 microarray led to the identification of one individual bearing a CNV that disrupted FLNA. FLNA-disrupting CNVs were also isolated in 2 other individuals by multiplex ligation probe amplification. These 3 cases were further characterized by high-resolution oligo array comparative genomic hybridization (CGH), and the precise junctional breakpoints of the rearrangements were identified by PCR amplification and sequencing.We report 3 cases of PNH caused by nonrecurrent genomic rearrangements that disrupt one copy of FLNA. The first individual carried a 113-kb deletion that removes all but the first exon of FLNA. A second patient harbored a complex rearrangement including a deletion of the 3' end of FLNA accompanied by a partial duplication event. A third patient bore a 39-kb deletion encompassing all of FLNA and the neighboring gene EMD. High-resolution oligo array CGH of the FLNA locus suggests distinct molecular mechanisms for each of these rearrangements, and implicates nearby low copy repeats in their pathogenesis.These results demonstrate that FLNA is prone to pathogenic rearrangements, and highlight the importance of screening for CNVs in individuals with PNH lacking FLNA point mutations.

SUBMITTER: Clapham KR

PROVIDER: S-EPMC3280053 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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FLNA genomic rearrangements cause periventricular nodular heterotopia.

Clapham K R KR Yu T W TW Ganesh V S VS Barry B B Chan Y Y Mei D D Parrini E E Funalot B B Dupuis L L Nezarati M M MM du Souich C C van Karnebeek C C Guerrini R R Walsh C A CA

Neurology 20120111 4

<h4>Objective</h4>To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNA sequencing is negative.<h4>Methods</h4>Screening of 35 patients from 33 pedigrees on an Affymetrix 6.0 microarray led to the identification of one individual bearing a CNV that disrupted FLNA. FLNA-disrupting CNVs were also isolated in 2 other individuals by multiplex ligation probe amplification. These 3 cases were further characterized by high-resolution oligo a ...[more]

PMID: 22238415

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Project description:Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established.Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients.Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age.We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.

Project description:BACKGROUND: X-linked periventricular nodular heterotopia is a disorder of neuronal migration resulting from mutations in the filamin A gene. This is an X-linked dominant condition where most affected patients are female and present with seizures. Extra-cerebral features such as cardiac abnormalities and thrombocytopenia have also been documented. Loss of function mutations in filamin A are predicted to result in prenatal lethality in males. Somatic mosaicism and mutations that lead to partial loss of function of the protein are hypothesized to explain viability of males reported in the literature. We report the first case of germline mosaicism involving a loss of function mutation in filamin A in a family where brain MRI, clinical exam, and mutation analysis is normal in both biological parents. CASE PRESENTATION: The index patient, a 39 year old female with normal development, had her first seizure at 24 years with no evidence of any precipitating factors. Brain MRI shows bilateral periventricular nodular heterotopia. She has thrombocytopenia and an echocardiogram at age 32 years revealed a mildly dilated aortic root and ascending aorta with mild aortic regurgitation. The second patient, the 36 year old younger sister of the index case, is currently healthy with no evidence of seizures or cardiac abnormalities. Her brain MRI is consistent with bilateral periventricular nodular heterotopia. The mother is healthy at 57 years of age with a normal brain MRI. The father is healthy at 59 years of age with a normal brain MRI. DNA sequencing of lymphocyte extracted DNA from the two sisters shows a c.2002C?>?T transition in exon 13 of filamin A resulting in a p.Gln668Ter mutation. This nonsense mutation was not detected in peripheral blood lymphocytes from the unaffected parents. CONCLUSION: This report provides evidence for germline mosaicism in filamin A-associated periventricular nodular heterotopia. This case must now be considered when providing genetic counseling to families where a proband presents as an isolated case and parental investigations are unremarkable.

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FLNA genomic rearrangements cause periventricular nodular heterotopia.

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FLNA genomic rearrangements cause periventricular nodular heterotopia.

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