Duplications of 17q12 can cause familial fever-related epilepsy syndromes

Hardies, Katia; Weckhuysen, Sarah; Peeters, Elke; Holmgren, Philip; Esch, Hilde Van; Jonghe, Peter De; Paesschen, Wim Van; Suls, Arvid

doi:10.1212/wnl.0b013e3182a84163

Cited by 25 publications

(25 citation statements)

References 34 publications

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“…It is hypothesized that the LHX1 gene is dosage‐sensitive and may be responsible for some of the neurocognitive (Nagamani et al, ) and urogenital phenotypes associated with 17q12 rearrangements. The duplication of the A CACA gene in the 17q12 region has also been implicated in the generation of neurodevelopmental symptoms, including seizures (Hardies et al, ). This gene is involved in acetyl‐CoA metabolism and its duplication would lead to overutilization of acetyl‐CoA which could result in a global energy failure of the brain.…”

Section: Discussionmentioning

confidence: 99%

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Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes

Kamath

Linden

Evans

et al. 2018

American J of Med Genetics Pt B

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Copy number variants at chromosome 17q12 have been associated with a spectrum of phenotypes. Deletions of 17q12 are well described and associated with maturity onset diabetes of the young type 5 (MODY5) and cystic renal disease (HNF1β) as well as cognitive impairment and seizures. Duplication of 17q12 is emerging as a new genetic syndrome, associated with learning disability, seizures, and behavioral problems. The duplication is often inherited from an apparently unaffected parent. Here, we describe a three-generation family with multiple individuals carrying a17q12 microduplication with varying clinical features, consistent with variable penetrance. The proband who inherited a 1.8 Mb interstitial 17q12 duplication from his mother presented with developmental delay, behavioral problems, and mild dysmorphism. One of his sisters, his maternal uncle, and his maternal grandmother also carry the 17q12 microduplication. Clinical features of the carriers include renal problems, diabetes mellitus, learning difficulties, epilepsy and mental illness. Cognitive abilities range from normal function to moderate impairment (full-scale IQ range: 52-99). In light of recent reports of association of this locus with schizophrenia, we performed a detailed psychiatric assessment and confirmed that one family member has symptoms consistent with a diagnosis of schizophrenia and another has a prodromal syndrome with attenuated positive symptoms of psychosis. This report extends the clinical phenotype associated with the 17q12 microduplication and highlights the phenotypic variability.

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Section: Discussionmentioning

confidence: 99%

“…Other associated phenotypes observed were behavioral problems, facial dysmorphisms, and abnormalities of the kidneys, esophagus, and genitalia (Bierhals, Maddukuri, Kutsche, & Girisha, ). A recent study also showed that 17q12 duplications are a rare cause of familial fever‐related epilepsy syndromes (Hardies et al, ).…”

Section: Introductionmentioning

confidence: 96%

Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes

Kamath

Linden

Evans

et al. 2018

American J of Med Genetics Pt B

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“…Pedigree 3 produced more varying results, with haplotypes definitely cosegregating in 17q12 and possibly cosegregating in 1q32.1 and 13q14.2. The 17q12 locus has been linked with generalized epilepsies and febrile seizures, as well as with migraines comorbid in Rolandic epilepsy (Sir en et al 2010;Hardies et al 2013;Addis et al 2014). Locus 1q32.1 contains two genes previously implicated in epilepsy: CAMSAP1L1 or calmodulin regulated spectrin-associated protein family, member 2 found in a GWAS of Chinese epilepsy patients (Guo et al 2012), and SRGAP2 or SLIT-ROBO Rho GTPase activating protein 2 in a single patient with early infantile epileptic encephalopathy and severe psychomotor disability (Saitsu et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

Wight

Nguyen

Medina³

et al. 2016

Molec Gen & Gen Med

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Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE/JME gene in 2q21.2–2q31.1, a JME/pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.

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“…This gene has gained attention primarily because mutations in this gene are associated with maturity‐onset diabetes of the young type 5 (MODY5), and renal cysts and diabetes syndrome (MIM#137920) [Bellanne‐Chantelot et al, ]. Also, LHX1 and ACACA have gained some attention as deficiency or duplication of these genes may be involved in neurodevelopmental symptoms [Nagamani et al, ; Hardies et al, ]. Furthermore, both LHX1 mutations and 17q12 deletions have been reported in patients with Mayer–Rokitansky–Kuster–Hauser syndrome (OMIM %277000) [Bernardini et al, ; Ledig et al, ].…”

Section: Introductionmentioning

confidence: 99%

“…So far, it has been proposed that the 17q12 deletion syndrome includes different renal diseases; endocrine, exocrine, and structural pancreatic abnormalities; liver cysts; elevation of liver enzymes; learning disability; macrocephaly; growth restriction; epilepsy; autism; structural brain abnormalities; behavioral abnormalities; schizophrenia; facial dysmorphism; neonatal transient hypercalcemia; congenital diaphragmatic hernia; duodenal atresia; prune belly syndrome (OMIM #100100); Müllerian aplasia; obesity; and joint laxity [Bellanne‐Chantelot et al, ; Mefford et al, ; Bernardini et al, ; Raile et al, ; Haeri et al, ; Moreno‐De‐Luca et al, ; Nagamani et al, ; Loirat et al, ; Dixit et al, ; Hendrix et al, ; Hinkes et al, ; Palumbo et al, ; Quintero‐Rivera et al, ; Goumy et al, ]. The 17q12 duplication syndrome has mainly been proposed to include autism, behavioral abnormalities, structural brain abnormalities, learning disability, epilepsy, schizophrenia, facial dysmorphism, renal disease, joint laxity, esophageal atresia, anal atresia, and endocrine abnormalities [Mefford et al, ; Nagamani et al, ; Faguer et al, ; Brandt et al, ; Bierhals et al, ; Hardies et al, ; Smigiel et al, ; Szatkiewicz et al, ; Mitchell et al, ].…”

Section: Introductionmentioning

confidence: 99%

17q12 deletion and duplication syndrome in Denmark—A clinical cohort of 38 patients and review of the literature

Rasmussen

Vestergaard

Graakjær

et al. 2016

American J of Med Genetics Pt A

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17q12 deletions and duplications are two distinct, recurrent chromosomal aberrations usually diagnosed by chromosomal microarray analysis (CMA). The aberrations encompass the genes, HNF1B, LHX1, and ACACA, among others. We here describe a large national cohort of 12 phenotyped patients with 17q12 deletions and 26 phenotyped patients with 17q12 duplications. The total cohort includes 19 index patients and 19 family members. We also reviewed the literature in order to further improve the basis for the counseling. We emphasize that renal disease, learning disability, behavioral abnormalities, epilepsy, autism, schizophrenia, structural brain abnormalities, facial dysmorphism, and joint laxity are features seen in both the 17q12 deletion syndrome and the reciprocal 17q12 duplication syndrome; and we extend the list of features seen in both patient categories to include strabismus, esophageal defects, and duodenal atresia. Delayed language development, learning disability, kidney involvement, and eye dysmorphism and strabismus were the most consistently shared features among patients with 17q12 deletion. Patients with 17q12 duplications were characterized by an extremely wide phenotypic spectrum, including a variable degree of learning disabilities, delayed language development, delayed motor milestones, and a broad range of psychiatric and neurological features. This patient group also included adults achieving an academic degree. Assessing index patients and non-index patients separately, our observations illustrate that an overall milder disease burden is seen, in particular in patients with 17q12 duplications who are ascertained on the duplication rather than the phenotype. This evidence may be useful in prenatal counseling. © 2016 Wiley Periodicals, Inc.

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Duplications of 17q12 can cause familial fever-related epilepsy syndromes

Cited by 25 publications

References 34 publications

Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes

Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

17q12 deletion and duplication syndrome in Denmark—A clinical cohort of 38 patients and review of the literature

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