FLNA genomic rearrangements cause periventricular nodular heterotopia.

OBJECTIVE: To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNA sequencing is negative. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.

Attention deficity/hyperactivity in SLI children increases risk of speech/language disorders in first-degree relatives: a preliminary report.

UNLABELLED: Specific language impairment (SLI) or developmental dysphasia denotes the inability to acquire normal expression and/or comprehension of language in the absence of peripheral hearing impairment, neurological disorder, and mental retardation. The presence of attention deficit/hyperactivity in some SLI children has previously been documented. This family history study used 27 SLI families, identified through the parents from the Dysphasia Association, to examine the relationship between attention deficit/hyperactivity in SLI children and the risk to first-degree relatives. All SLI children were clinically diagnosed with speech/language disorder; medical records were searched for the presence of any of the exclusion criteria noted above. The 13 SLI children with medical record of attention deficit/hyperactivity had a significantly higher chance of having first-degree relatives with speech/language disorders than 14 SLI children without such record (15/27 and 4/46, respectively). This preliminary report suggests that additional study is warranted to investigate the relationship between speech/language disorders and attention deficit/hyperactivity in families of SLI children. LEARNING OUTCOMES: As a result of this activity, the participant will be able to describe the SLI phenotype, its prevalence, and complexity and to recognize the relationship between comorbid attention deficit/hyperactivity in SLI children and the risk of speech/language disorder in their relatives.

Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada.

Familial hypercholesterolemia (FH) is caused by mutations in the LDL receptor (LDLR) gene and is usually associated with hypercholesterolemia, lipid deposition in tissues, and premature coronary artery disease (CAD). However, individuals with heterozygous FH in China exhibit a milder phenotype despite having deleterious mutations in the LDLR gene (X.-M. Sun et al, Arterioscler Thromb. 1994;14:85-94). Nineteen Chinese FH heterozygotes living in Canada were screened for the 11 mutations that had been described in FH patients living in China. One Chinese Canadian carried one of these mutations (Trp462Stop), 2 carried a previously unreported single-base substitution (Cysl63Arg), and 1 carried a mutation observed in French-Canadian patients (Glu207Lys). Twelve additional carriers of these mutations were identified in the families of the index patients. Significantly higher LDL cholesterol concentrations were observed in FH heterozygotes with defined mutations living in Canada (mean+/-SD, 7.46+/-1.29, n=16) than in those living in China (4.35+/-1.09, n=18; P<.0001). Six of the 16 FH heterozygotes residingin Canada had evidence of tendon xanthomata and 4 had a history of premature CAD, whereas none of those in China had tendon xanthomata or CAD. Complete segregation between hypercholesterolemia and inheritance of a mutant allele was observed in 3 Canadian Chinese FH families. Thus, Chinese FH heterozygotes living in Canada exhibit a phenotype similar to that of other FH patients in Western societies. The difference between patients living in Canada and those living in China could be ascribed to differences in dietary fat consumption, showing that environmental factors such as diet play a significant role in modulating the phenotype of heterozygous FH.