Transmitted duplication of 8p23.1-8p23.2 associated with speech delay, autism and learning difficulties

Duplications of distal 8p with and without significant clinical phenotypes have been reported and are often associated with an unusual degree of structural complexity. Here, we present a duplication of 8p23.1-8p23.2 ascertained in a child with speech delay and a diagnosis of ICD-10 autism. The same duplication was found in his mother who had epilepsy and learning problems. A combination of cytogenetic, FISH, microsatellite, MLPA and oaCGH analysis was used to show that the duplication extended over a minimum of 6.8 Mb between 3 539 893 and 10 323 426 bp. This interval contains 32 novel and 41 known genes, of which only microcephalin (MCPH1) is a plausible candidate gene for autism at present. The distal breakpoint of the duplicated region interrupts the CSMD1 gene in 8p23.2 and the medial breakpoint lies between the MSRA and RP1L1 genes in 8p23.1.An interchromosomal insertion between a normal and polymorphically inverted chromosome 8 is proposed to explain the origin of this duplication. Further mapped imbalances of distal 8p are needed to determine whether the autistic component of the phenotype in this family results from the cumulative imbalance of many genes or dosage imbalance of an individual susceptibility gene.     

Direct duplication of 8p21.3→p23.1: A cytogenetic anomaly associated with developmental delay without consistent clinical features

We report six cases in two families and a sporadic case with a direct duplication of region 8p21.3→23.1. In one family, the duplication started in the mother and was transmitted to one son and one daughter. In the second family, the father was mosaic for the anomaly that was transmitted to his two daughters. The cytogenetic anomaly was initially described as an 8p+ with banding analysis and then delineated with fluorescence in situ hybridization (FISH) using whole‐chromosome 8 painting, 8p specific painting, and 8p or 8p/8q subtelomeric probes. Deletion was not detected in the subtelomeric region of the abnormal chromosome 8 examined in one family and in the sporadic case. The phenotypic picture varies from normal to moderate mental retardation in the affected individuals. No consistent minor anomalies or congenital defects were observed among these cases. After comparing the chromosome region involved in our cases with those in others having direct or inverted duplications of 8p, it is thought that the segment 8p21.1→21.3 might be the critical region for an 8p duplication syndrome. The parental origin of the duplication does not seem to impact its clinical significance. © 2001 Wiley‐Liss, Inc.     

20‐Mb duplication of chromosome 9p in a girl with minimal physical findings and normal IQ: Narrowing of the 9p duplication critical region to 6 Mb

We studied the case of a girl with a partial 9p duplication, dup(9)(p22.1 → p13.1). Molecular cytogenetics studies defined the chromosome 9 rearrangement as a direct duplication of 20 Mb from D9S1213 to D9S52. Microsatellite analysis demonstrated the presence of a double dosage of the paternal alleles and demonstrated that the duplication occurred between sister chromatids. The patient's phenotype was almost normal, with a few minor anomalies (dolichocephaly, crowded teeth, high arched palate) and normal IQ. The breakpoint's location in this patient and previously reported cases suggest that the critical region for the 9p duplication syndrome lies within a 6‐Mb portion of chromosome 9p22 between markers D9S267 and D9S1213. © 2002 Wiley‐Liss, Inc.     

一例8P倒位重复伴末端缺失综合征的细胞和分子遗传学研究

目的 明确1例智力低下患儿8号染色体短臂异常的片段来源和位置,探讨该异常核型的发生机制、临床表型特征和家庭再发风险.方法 高分辨显带分析患者及其父母外周血染色体核型,比较基因组杂交芯片(array comparative genomic hybridization,array CGH)精细定位拷贝数异常改变的染色体片段区域,荧光定量PCR验证芯片分析结果.结果 患儿异常染色体为8p11.2-p23.1倒位重复和8p23.2-pter缺失;在重复和缺失之间间隔有1个长为5.70 Mb的拷贝数正常片段,嗅觉受体(olfactory receptor,OR)基因簇位于该片段的两端.结论 这是1例典型的inv dup del(8p)综合征,临床上以重度智力低下、大脑发育不良和特殊面容为主要特征,由8p23.1上OR基因簇的重复序列发生非等位同源重组所致.再生育时,不仅要预防inv dup del(8p)的再发风险,还要注意由同一重组机制造成的另外3种不良结局的妊娠风险.就目前所知,这是国内第1例明确诊断的inv dup del(8p)综合征.     

8p23.1 duplication syndrome; common,confirmed, and novel features in six further patients

The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124‐1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000. © 2013 Wiley Periodicals, Inc.     

Inverted duplication of 8p: Ten new patients and review of the literature

We evaluated 10 patients with an inverted tandem duplication of 8p. Inverted duplications of chromosome 8 have been reported infrequently, and no syndrome has been previously identified. All 8 patients on whom birth histories were available were hypotonic at birth, and had feeding difficulties in the neonatal period. All patients have significant developmental delay. Manifestaions present in 5 or more patients were prominent forehead, high arched palate, large mouth with a thin upper lip, malformed and/or apparently lowset ears, broad nasal bridge, dental and skeletal abnormalities, and joint laxity or hyperextensibility. Variation in the phenotype may, in part, be explained by the different breakpoints. Recurrence risks of de novo rearrangements are probably very low, but for the recombinants the risk may be significant. The duplication appeared to be de novo in 6 patients (both parental karyotypes were normal); maternal karyotypes were normal in 2 patients, and both parrents of 1 patient were not available. One propositus had a monocentric recombinant of a paracentric inv(8) (p12p23.3) carried by the mother, and is one of only 6 known cases of duplication associated with a balanced paracentric inversion in a parent. The carrier parent was the mother in 5 of those 6 cases. Each case involved a different chromosome, and each probably was created by an unusual meiotic recombination event. Inverted duplication 8p is one of the most common duplications observed in our laboratories, and ranks in frequency with the classical deletions, such as Wolf-Hirschhorn and cri-du-chat syndromes and duplication or secondary trisomy 15ql. Since 1/7 cases with complete parental karyotypes was associated with a familial rearrangement, parental karyotype studies should be considered in all cases of tandem duplication. © 1993 Wiley-Liss, Inc.     

Consideration of the haplotype diversity at nonallelic homologous recombination hotspots improves the precision of rearrangement breakpoint identification

Precise characterization of nonallelic homologous recombination (NAHR) breakpoints is key to identifying those features that influence NAHR frequency. Until now, analysis of NAHR‐mediated rearrangements has generally been performed by comparison of the breakpoint‐spanning sequences with the human genome reference sequence. We show here that the haplotype diversity of NAHR hotspots may interfere with breakpoint‐mapping. We studied the transmitting parents of individuals with germline type‐1 NF1 deletions mediated by NAHR within the paralogous recombination site 1 (PRS1) or paralogous recombination site 2 (PRS2) hotspots. Several parental wild‐type PRS1 and PRS2 haplotypes were identified that exhibited considerable sequence differences with respect to the reference sequence, which also affected the number of predicted PRDM9‐binding sites. Sequence comparisons between the parental wild‐type PRS1 or PRS2 haplotypes and the deletion breakpoint‐spanning sequences from the patients (method #2) turned out to be an accurate means to assign NF1 deletion breakpoints and proved superior to crude reference sequence comparisons that neglect to consider haplotype diversity (method #1). The mean length of the deletion breakpoint regions assigned by method #2 was 269‐bp in contrast to 502‐bp by method #1. Our findings imply that paralog‐specific haplotype diversity of NAHR hotspots (such as PRS2) and population‐specific haplotype diversity must be taken into account in order to accurately ascertain NAHR‐mediated rearrangement breakpoints.     

Clinical and cytogenetic findings in seven cases of inverted duplication of 8p with evidence of a telomeric deletion using fluorescence in situ hybridization

We report on the clinical and cytogenetic findings in 7 cases of inverted duplication of region 8p11.2-p23. The phenotype of inv dup (8p) compiled from this series and the literature (N = 29) consists of severe mental retardation (100%), minor facial alterations (97%), agenesis of the corpus callosum (80%), hypotonia (66%), orthopedic abnormalities (58%), scoliosis/kyphosis (40%), and congenital heart defect (26%). A telomeric deletion of region 8p23.3-pter was confirmed in 3 of our cases studied using fluorescent in situ hybridization with a telomeric probe for 8p. Thus, these karyotypes are inv dup del(8) (qter→p23.1::p23.1→p11.2:). Our findings sugest that most cases of inv dup(8p) probably have a telomeric deletion. © 1995 Wiley-Liss, Inc.     

Co‐existence of 9p deletion and Silver‐Russell syndromes in a patient with maternally inherited cryptic complex chromosome rearrangement involving chromosomes 4, 9, and 11

We report a patient with a maternally inherited unbalanced complex chromosomal rearrangement (CCR) involving chromosomes 4, 9, and 11 detected by microarray comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). This patient presents with clinical features of 9p deletion syndrome and Silver‐Russell syndrome (SRS). Chromosome analysis performed in 2000 showed what appeared to be a simple terminal deletion of chromosome 9p22.1. aCGH performed in 2010 revealed a 1.63 Mb duplication at 4q28.3, a 15.48 Mb deletion at 9p24.3p22.3, and a 1.95 Mb duplication at 11p15.5. FISH analysis revealed a derivative chromosome 9 resulting from an unbalanced translocation between chromosomes 9 and 11, a chromosome 4 fragment inserted near the breakpoint of the translocation. The 4q28.3 duplication does not contain any currently known genes. The 9p24.3p22.3 deletion region contains 36 OMIM genes including a 3.5 Mb critical region for the 9p‐phenotype. The 11p15.5 duplication contains 49 OMIM genes including H19 and IGF2. Maternal aCGH was normal. However, maternal chromosomal and FISH analyses revealed an apparently balanced CCR involving chromosomes 4, 9, and 11. To the best of our knowledge, this is the first report of a patient with maternally inherited trans‐duplication of the entire imprinting control region 1 (ICR1) among the 11p15.5 duplications reported in SRS patients. This report supports the hypothesis that the trans‐duplication of the maternal copy of ICR1 alone is sufficient for the clinical manifestation of SRS and demonstrates the usefulness of combining aCGH with karyotyping and FISH for detecting cryptic genomic imbalances. © 2012 Wiley Periodicals, Inc.     

De novo deletions and duplications detected by array CGH: a study of parental origin in relation to mechanisms of formation and size of imbalance

We report a large series of 173 patients with physical and/or neurological abnormalities and a de novo imbalance identified by array CGH. Breakpoint intervals were screened for the presence of low copy repeats (LCRs) to distinguish between rearrangements formed by non-allelic homologous recombination (NAHR) and rearrangements formed by other mechanisms. We identified significant differences in size and parental origin between the LCR-mediated and non-LCR groups. Non-LCR imbalances were evenly distributed among the four size intervals we defined, whereas LCR-mediated rearrangements had a narrow size distribution, predominantly between 1 and 5 Mb (P = 0.001). Among the LCR-mediated rearrangements there were equal numbers of maternally and paternally derived cases. In contrast, for the non-LCR rearrangements there was a significant excess of paternal cases (P = 0.024) over a wide size range including below 1 Mb. Our results provide novel evidence that unbalanced chromosome rearrangements are not only more frequent in males, but may also arise through different mechanisms than those seen in females. Although the paternal imbalances identified in our study are evenly distributed throughout the four size groups, there are very few maternal imbalances either <1 Mb or >10 Mb. Furthermore, a lower proportion of paternal imbalances are LCR mediated (13/71) compared with the maternal imbalances (12/30). We hypothesise that imbalances of maternal origin arise predominantly through NAHR during meiosis, while the majority of imbalances of paternal origin arise through male-specific mechanisms other than NAHR. Our data suggest that mitotic mechanisms could be important for the formation of chromosome imbalances; however, we found no association with increased paternal age.