Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities.

The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance, and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.

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.

Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.

BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH.

The 8p23.1 deletion syndrome is established but not an equivalent duplication syndrome. Here, we report five patients; a de novo prenatal case and two families in which 8p23.1 duplications have been directly transmitted from mothers to children. Dual-colour fluorescent in situ hybridisation, multiplex ligation-dependent probe amplification analysis and customised oligonucleotide array comparative genomic hybridisation (oaCGH) indicated an approximately 3.75 Mb duplication of most of band 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) in all cases. However, oaCGH revealed an additional duplication of 500 kb adjacent to the proximal ORDR in Family 1 and an additional deletion of 3.14 Mb within the Nablus Mask-Like Facial Syndrome region of 8q22.1 in Family 2. Copy number variation at introns 4-5 of the GATA4 gene was also identified. This 8p23.1 duplication syndrome is associated with a characteristic facial phenotype including a prominent forehead and arched eyebrows. Adrenal insufficiency, Tetralogy of Fallot, partial 2/3 syndactyly of the toes and cleft palate in some individuals may be explained by ascertainment bias, incomplete penetrance and/or the presence of the microdeletion in Family 2. The duplication is compatible with normal early childhood development but, although our adult cases live independent lives with varying degrees of support, learning difficulties have been experienced by some family members. We conclude that the 8p23.1 duplication syndrome is a genomic condition with an emerging but variable phenotype that may be under-diagnosed. Our results demonstrate that direct transmission does not distinguish genuine duplications from euchromatic variants and illustrate the power of array CGH to reveal unexpected additional imbalances in affected patients.

Deletions of 2q14 that include the homeobox engrailed 1 (EN1) transcription factor are compatible with a normal phenotype.

A novel transmitted 2-3 Mb deletion of 2q14.1-q14.2 was found in an affected boy from a consanguineous family with a possible diagnosis of PEHO syndrome (OMIM 260565). BAC FISH showed that the deletion included a minimum of 20 genes including the homeobox engrailed 1 gene (EN1). However, the same deletion was also found in his phenotypically normal father and brother (family 1). The phenotype of the proband may, therefore, have been coincidental to the deletion, a result of a recessive condition within or outside the deleted segment or possibly due to variable dosage compensation of EN1 by the paralogous EN2 gene at 7q36. BAC FISH also showed that this deletion overlapped with a previously reported transmitted deletion of 2q13-q14.1 that had no phenotypic consequences (family 2). The deleted regions contained a total of 32 genes and comprise the final 5.25 Mb of the ancestral chromosome 2B from which chromosome 2 was formed in man. These families provide further evidence that heterozygous deletions of regions of low gene density are compatible with a normal phenotype.

16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2.

Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.

8p23.1 duplication syndrome differentiated from copy number variation of the defensin cluster at prenatal diagnosis in four new families.

BACKGROUND: The 8p23.1 duplication syndrome and copy number variation of the 8p23.1 defensin gene cluster are cytogenetically indistinguishable but distinct at the molecular level. To our knowledge, the 8p23.1 duplication syndrome has been described at prenatal diagnosis only once and we report our experience with four further apparent duplications ascertained at prenatal diagnosis. METHODS: Additional material at band 8p23.1 was detected using conventional G-banded cytogenetics in each case. Multiplex Ligation-dependent Probe Amplification (MLPA) or Fluorescence In Situ Hybridisation (FISH) were used depending on whether only DNA (Cases 1 and 4) or cytogenetic preparations (Cases 2 and 3) were available from the laboratory of origin. The extent of the duplication in Case 1 was retrospectively determined using array Comparative Genomic Hybridisation (array CGH). RESULTS: Three cases of 8p23.1 duplication syndrome were found (Cases 1 to 3). Two were de novo and continued to term and the third, a paternally transmitted duplication, was terminated because of a previous child with psychomotor delay and 8p23.1 duplication syndrome. Case 1 was ascertained with a hypoplastic left heart but the ventricular septal and interventricular defects, in Cases 2 and 3 respectively, were found after ascertainment for advanced maternal age. By contrast, case 4 was a maternally transmitted copy number variation of the defensin cluster with normal outcome. CONCLUSIONS: Our data underline the need to differentiate 8p23.1 duplications from copy number variation of the defensin cluster using FISH, MLPA or array CGH. Cardiac defects were ascertained by ultrasound in only one of the three duplication 8p23.1 pregnancies but were visible in two of the three at 21 to 22 weeks gestation. Our results provide further evidence that both deletion and duplication of the GATA4 transcription factor can give rise to a variety of conotruncal heart defects with variable penetrance and expressivity.

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.