Wolf-Hirschhorn Syndrome Critical Region Research Articles

The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.

NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain-of-function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch-Steindl syndrome (RAUST).

The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy

BackgroundWolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants.MethodsIn our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature.ResultsA novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years.ConclusionsHere we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.

Wolf-Hirschhorn Syndrome-Associated Genes Are Enriched in Motile Neural Crest Cells and Affect Craniofacial Development in Xenopus laevis.

Wolf-Hirschhorn Syndrome (WHS) is a human developmental disorder arising from a hemizygous perturbation, typically a microdeletion, on the short arm of chromosome four. In addition to pronounced intellectual disability, seizures, and delayed growth, WHS presents with a characteristic facial dysmorphism and varying prevalence of microcephaly, micrognathia, cartilage malformation in the ear and nose, and facial asymmetries. These affected craniofacial tissues all derive from a shared embryonic precursor, the cranial neural crest (CNC), inviting the hypothesis that one or more WHS-affected genes may be critical regulators of neural crest development or migration. To explore this, we characterized expression of multiple genes within or immediately proximal to defined WHS critical regions, across the span of craniofacial development in the vertebrate model system Xenopus laevis. This subset of genes, whsc1, whsc2, letm1, and tacc3, are diverse in their currently-elucidated cellular functions; yet we find that their expression demonstrates shared tissue-specific enrichment within the anterior neural tube, migratory neural crest, and later craniofacial structures. We examine the ramifications of this by characterizing craniofacial development and neural crest migration following individual gene depletion. We observe that several WHS-associated genes significantly impact facial patterning, cartilage formation, neural crest motility in vivo and in vitro, and can separately contribute to forebrain scaling. Thus, we have determined that numerous genes within and surrounding the defined WHS critical regions potently impact craniofacial patterning, suggesting their role in WHS presentation may stem from essential functions during neural crest-derived tissue formation.

Natural histories of patients with Wolf-Hirschhorn syndrome derived from variable chromosomal abnormalities.

Wolf-Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype-phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause "typical WHS facial appearance". In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted-duplication-deletion. Among 10 patients, one patient did not show "typical WHS facial appearance" although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited "typical WHS facial appearance" although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.

Gene interaction network analysis within the 4P16.3 critical region

Deletions in the 4p16.3 region cause Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome involving variable size deletions. This study aimed to perform a gene interaction network analysis within the WHS critical region and to stablish the cytogenomic profile of the chromosome rearrangements involving the 4p16.3 regions. 16 samples from individuals with a clinical indication of WHS were retrospectively analyzed of which 11 had a cytogenetic visible deletion and 5 a submicroscopic deletion not previously identified. Using FISH, chromosomal microarray analysis, WGS and WES, we define the critical breakpoints within the 4p16.3 chromosome rearrangements. A gene interaction network analysis was performed using the Cytoscape (http://apps.cytoscape.org) platform.In addition to 12 terminal deletions, we mapped 1 interstitial deletion, 2 ring chromosomes and 1 typical translocation 4;8. The deletions sizes ranged between 3.7 and 25.6 Mb. We present the genotype-phenotype correlation for each patient and characterize the type, the extension and the genomic position of the chromosome rearrangements as well. Previous genotype-phenotype correlations of the 4p16.3 regions have been hampered by the presence of other imbalances leading to duplication in part of the WHS critical region, which was a confounding factor in some of these correlations. In this study, only patients with 4p deletion due to different types of chromosome rearrangements were included, which enabled us to further refine the 4p critical region map and to explore new insights on mechanisms associated with CNVs within the 4p16.3 regions. The individuals in our study whose deletions encompass the terminal 875 kb 4p16.3 region were reported as having microcephaly and seizures, typical in the clinical context of the WHS. Focusing on the chromosome critical region defined in our sample, we explore, molecular interaction networks and biological pathways involving genes associated with the WHS.

Wolf-Hirschhorn Syndrome (WHS), A Case Report and Review of Literature Submit Manuscript

Background: Wolf-Hirschhorn Syndrome (WHS) is a congenital malformation syndrome characterized by growth deficiency and varying developmental delays based on genomic deletions and characteristic facies. The majority of WHS cases are caused by a deletion of 4p16.3 regions on chromosome 4, which includes the Wolf-Hirschhorn Syndrome Candidate genes (WHSC1 and WHSC2). WHSC1 protein is required to inhibit DNA damage by regulating the methylation of histones. The diagnosis of WHS is established by detection of a heterozygous deletion of the Wolf-Hirschhorn Syndrome Critical Region (WHSCR) with 4p16.3 at approximately 1.4-1.9 kb from the terminus. The WHSCR region is restricted to a 165-kb interval in the 4p16.3. Some of the associated structural defects, such as cleft lip and palate, occur more frequently in individuals with greater than 3 megabase (Mb) deletions. The quantity of base deletions is an important factor in explaining phenotypic variability WHS. The deletion size has a partial correlation to severity, but not a direct correlation, as the phenotypic affect may be more or less severely affected than would be expected by the size of the deleted megabase. Most individuals affected by this disorder have distinctive facial features, such as a broad, flat nasal bridge and a high forehead described as the “Greek warrior helmet” appearance in which the eyes are protruding and widely spaced. Other facial features include a shortened distance between the nose and the upper lip (a short philtrum), a down-turned mouth, a small chin (micrognathia), poorly formed ears with small holes (pits) of flaps of skin (tags), a small head (microcephaly). Intellectual disability ranges from mild to severe in people with WHS. Compared to people with other forms of intellectual disability, their socialization skills are strong, while verbal, communication, and language skills tend to be weaker. Case: We present the identification during routine obstetric sonographic imaging of growth restricted fetus affected by WHS with co-morbid oligohydramnios and abnormal prenatal obstetrics ultrasound studies, which showed micrognathia, echogenic kidneys and echogenic bowel, in addition to a three-week discrepancy between the estimated ultrasound age and the gestational age by last menstrual period (LMP), compatible with intrauterine growth restriction (IUGR). Prenatal genetic testing demonstrated female karyotype with a satellite chromosome on chromosome 4 short arm and mosaicism for an additional marker chromosome (47, XX, 4ps, +mar (8)/46, XX, 4ps). The prenatal diagnostic approach included fetal sonographic assessment and molecular cytogenetic investigation. After engaging in a multidisciplinary informed consent process at our institution, the patient chose to continue prenatal care and not electively terminate the pregnancy. Conclusion: A 4p deletion on chromosome 4 can be associated with subtle chromosome imbalances in other chromosomes. For example, the t(4;8)(p16;p23) translocation may be undetected in routine cytogenetics, suggesting that this translocation may be more the most frequent translocation after the most common reciprocal translocation in humans, t(11q;22q). The extent of the Mb deleted within the 4p region located on chromosome 4 correlates with the severity of the WHS phenotype. Genetic counseling provides families with information on the nature and implications of inherited genetic disorders, as a means of facilitating shared health care decisions.

A large Indian family with rearrangement of chromosome 4p16 and 3p26.3 and divergent clinical presentations

BackgroundThe deletion of the chromosome 4p16.3 Wolf-Hirschhorn syndrome critical region (WHSCR-2) typically results in a characteristic facial appearance, varying intellectual disability, stereotypies and prenatal onset of growth retardation, while gains of the same chromosomal region result in a more variable degree of intellectual deficit and dysmorphism. Similarly the phenotype of individuals with terminal deletions of distal chromosome 3p (3p deletion syndrome) varies from mild to severe intellectual deficit, micro- and trigonocephaly, and a distinct facial appearance.Methods and resultsWe investigated a large Indian five-generation pedigree with ten affected family members in which chromosomal microarray and fluorescence in situ hybridization analyses disclosed a complex rearrangement involving chromosomal subregions 4p16.1 and 3p26.3 resulting in a 4p16.1 deletion and 3p26.3 microduplication in three individuals, and a 4p16.1 duplication and 3p26.3 microdeletion in seven individuals. A typical clinical presentation of WHS was observed in all three cases with 4p16.1 deletion and 3p26.3 microduplication. Individuals with a 4p16.1 duplication and 3p26.3 microdeletion demonstrated a range of clinical features including typical 3p microdeletion or 4p partial trisomy syndrome to more severe neurodevelopmental delay with distinct dysmorphic features.ConclusionWe present the largest pedigree with complex t(4p;3p) chromosomal rearrangements and diverse clinical outcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome amongst affected individuals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0251-5) contains supplementary material, which is available to authorized users.

Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

BackgroundApparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.MethodsEighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.ResultsWe detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.ConclusionsThese findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

Microarray and FISH‐based genotype–phenotype analysis of 22 Japanese patients with Wolf–Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome of the distal 4p chromosome, characterized by craniofacial features, growth impairment, intellectual disability, and seizures. Although genotype-phenotype correlation studies have previously been published, several important issues remain to be elucidated including seizure severity. We present detailed clinical and molecular-cytogenetic findings from a microarray and fluorescence in situ hybridization (FISH)-based genotype-phenotype analysis of 22 Japanese WHS patients, the first large non-Western series. 4p deletions were terminal in 20 patients and interstitial in two, with deletion sizes ranging from 2.06 to 29.42 Mb. The new Wolf-Hirschhorn syndrome critical region (WHSCR2) was deleted in all cases, and duplication of other chromosomal regions occurred in four. Complex mosaicism was identified in two cases: two different 4p terminal deletions; a simple 4p terminal deletion and an unbalanced translocation with the same 4p breakpoint. Seizures began in infancy in 33% (2/6) of cases with small (<6 Mb) deletions and in 86% (12/14) of cases with larger deletions (>6 Mb). Status epilepticus occurred in 17% (1/6) with small deletions and in 87% (13/15) with larger deletions. Renal hypoplasia or dysplasia and structural ocular anomalies were more prevalent in those with larger deletions. A new susceptible region for seizure occurrence is suggested between 0.76 and 1.3 Mb from 4 pter, encompassing CTBP1 and CPLX1, and distal to the previously-supposed candidate gene LETM1. The usefulness of bromide therapy for seizures and additional clinical features including hypercholesterolemia are also described.

109 kb deletion of chromosome 4p16.3 in a patient with mild phenotype of Wolf–Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome associated with growth retardation, developmental disabilities, epileptic seizures, and distinct facial features resulting from a deletion of the short arm of chromosome 4. The Wolf-Hirschhorn Syndrome Critical Region WHSCR2 includes the LETM1 gene and 5' end of the WHSC1 gene. A haploinsufficiency of WHSC1 is thought to be responsible for a number of WHS characteristics. We report on a 2-year-old male with severe growth retardation, microcephaly and a characteristic facial appearance. He had no internal anomalies and his developmental milestones were mildly delayed. An array-CGH analysis revealed loss of genomic copy numbers in the region 4p16.3, which included FGFR3, LETM1, and WHSC1. The size of the deletion was only 109 kb. The deletion included the important genes in WHSCR2. We suspect that haploinsufficiency of WHSC1 is the most probable cause of the growth deficiency, microcephaly, and characteristic facial features in WHS.

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf-Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region.

Wolf–Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage

Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with growth retardation, mental retardation, and immunodeficiency resulting from a hemizygous deletion of the short arm of chromosome 4, called the WHS critical region (WHSC). The WHSC1 gene is located in this region, and its loss is believed to be responsible for a number of WHS characteristics. We identified WHSC1 in a genetic screen for genes involved in responding to replication stress, linking Wolf-Hirschhorn syndrome to the DNA damage response (DDR). Here, we report that the WHSC1 protein is a member of the DDR pathway. WHSC1 localizes to sites of DNA damage and replication stress and is required for resistance to many DNA-damaging and replication stress-inducing agents. Through its SET domain, WHSC1 regulates the methylation status of the histone H4 K20 residue and is required for the recruitment of 53BP1 to sites of DNA damage. We propose that Wolf-Hirschhorn syndrome results from a defect in the DDR.

Microduplication of 4p16.3 due to an unbalanced translocation resulting in a mild phenotype

With the widespread clinical use of comparative genomic hybridization chromosomal microarray technology, several previously unidentified clinically significant submicroscopic chromosome abnormalities have been discovered. Specifically, there have been reports of clinically significant microduplications found in regions of known microdeletion syndromes. In general, these microduplications have distinct features from those described in the corresponding microdeletion syndromes. We present a 5½-year-old patient with normal growth, borderline normal IQ, borderline hypertelorism, and speech and language delay who was found to have a submicroscopic 2.3 Mb terminal duplication involving the two proposed Wolf-Hirschhorn syndrome (WHS) critical regions at chromosome 4p16.3. This duplication was the result of a maternally inherited reciprocal translocation involving the breakpoints 4p16.3 and 17q25.3. Our patient's features are distinct from those described in WHS and are not as severe as those described in partial trisomy 4p. There are two other patients in the medical literature with 4p16.3 microduplications of similar size also involving the WHS critical regions. Our patient shows clinical overlap with these two patients, although overall her features are milder than what has been previously described. Our patient's features expand the knowledge of the clinical phenotype of a 4p16.3 microduplication and highlight the need for further information about it.

C4ORF48, a gene from the Wolf-Hirschhorn syndrome critical region, encodes a putative neuropeptide and is expressed during neocortex and cerebellar development

In order to identify novel genes involved in mental retardation/intellectual disability, we focused on a microdeletion reported in a patient with a mild form of Wolf-Hirschhorn syndrome. This patient presented with attention-deficit hyperactivity disorder, some learning and fine motor deficits as well as facial abnormalities. The deleted region included three genes. Here, we report the first characterization of one of these genes, C4ORF48. C4ORF48 encodes a short (139 aa) evolutionarily conserved protein with a predicted signal peptide and two potential dibasic convertase cleavage sites. In mice, we demonstrated expression of the corresponding protein exclusively in brain tissue using an anti-mouse C4Orf48 polyclonal antibody. Detailed RNA in situ hybridization experiments revealed expression of C4Orf48 in different zones during cortical and cerebellar development, as well as in almost all cortical and subcortical regions of the adult mouse brain. Based on the present data, we propose that C4Orf48 probably encodes a novel neuropeptide, which, if hemizygously deleted, may be involved in the observed intellectual and fine motor disabilities and thus in the overall neurological aspects of Wolf-Hirschhorn syndrome.

Duplication of the Wolf-Hirschhorn syndrome critical region causes neurodevelopmental delay

Wolf-Hirschhorn Syndrome (WHS) is caused by deletions on chromosome 4p and is clinically well defined. Genotype-phenotype correlations of patients with WHS point to a critical locus to be responsible for the main characteristics of this disorder. Submicroscopic duplications of this region, however, are not known. Here we report a patient with an interstitial 560 kb duplication overlapping this critical locus. The present case shows that not only deletions but also duplications of the Wolf-Hirshhorn critical region cause mental retardation and multiple congenital anomalies. Interestingly, the duplication phenotype overlaps partially with the deletion phenotype. However, his facial phenotype differs from the typical WHS gestalt.

“Essentially” pure trisomy 3q27 → qter: Further delineation of the partial trisomy 3q phenotype

Partial duplication 3q is a well defined clinical entity characterized by growth retardation, cryptorchism, microcephaly, and characteristic dysmorphisms. Most patients present with large duplications or are associated with a second chromosomal imbalance, which makes the definition of the phenotype difficult. Here, we report on a 4-year and 8-month-old girl with pre- and postnatal measurements in the high normal range, developmental delay, minor dysmorphic features, and a de novo unbalanced 3/4 translocation with trisomy 3q27 --> qter and monosomy of the subtelomeric region of 4p. Conventional karyotyping, FISH with probes from the Wolf-Hirschhorn syndrome critical region and chromosome 4p locus-specific probes, microsatellite marker-based haplotyping, and SNP microarray copy number analysis revealed a terminal 4p deletion of less than 500 kb with a breakpoint distal to the Wolf-Hirschhorn syndrome critical region, a chromosome 3q duplication of around 15.3 Mb, with origin of the rearrangement in paternal meiosis. Thus, our case clearly characterizes the phenotype of pure partial duplication 3q more exactly, and moreover, indicates that small chromosome rearrangements might lead to growth in the upper normal range or even cause overgrowth.

Microdeletion 4p16.3 that includes Wolf-Hirschhorn syndrome critical region – A case report

Microdeletion 4p16.3 that includes Wolf-Hirschhorn syndrome critical region – A case report

Pathogenic significance of deletions distal to the currently described Wolf–Hirschhorn syndrome critical regions on 4p16.3

Within recent years, numerous individuals have been identified with terminal 4p microdeletions distal to the currently described critical regions for the Wolf-Hirschhorn syndrome (WHS). Some of these individuals do not display features consistent with WHS whereas others have a clinical phenotype with some overlap to the WHS phenotype. In this review we discuss the genetic and clinical presentation of these cases in an attempt to understand the consequence of monosomy of the genes distal to the proposed critical regions and identify the distal boundary for pathogenic genes involved in components of the WHS phenotype.

Mouse models of Wolf–Hirschhorn syndrome

Subtelomeric deletion syndromes represent a significant cause of mental retardation and craniofacial disease. However, for most of these syndromes the pathogenic genes have yet to be identified. Currently there is every indication that identification of these genes will be a slow process if we continue to rely strictly upon clinical data. An alternative approach is the use of mouse models to complement the patient studies. Wolf-Hirschhorn syndrome (WHS), caused by deletions in 4p16.3, is the first recognized subtelomeric deletion syndrome. As with other syndromes of this class, WHS has not yet been subjected to an intensive, systematic analysis using mouse models. Nonetheless, a significant number of targeted mutations have been introduced into mouse genomic region, 5B1, which is orthologous to 4p16.3. Included among these mutations are a series of deletions approximating the deletions in some patients. The mouse lines carrying these deletions display a remarkable concordance of phenotypes with the human patient's characteristics, strongly indicating that the mouse models can be used to phenocopy WHS. In this review, we will catalog the currently existing targeted mutations in mice in the regions orthologous to the WHS critical regions. For each mutation we will discuss the resulting phenotype and its potential relevance to the pathogenesis of the syndrome. Further, we will describe how the phenotypes of some of the mutations suggest new directions for the clinical studies. Finally we will outline approaches for the efficient creation of new mouse models of WHS going forward.

Co‐occurrence of 4p16.3 deletions with both paternal and maternal duplications of 11p15: Modification of the Wolf–Hirschhorn syndrome phenotype by genetic alterations predicted to result in either a Beckwith–Wiedemann or Russell–Silver phenotype

Paternal duplications of chromosome region 11p15 can result in Beckwith-Weidemann syndrome (BWS), whereas maternal duplications of the same region on 11p15 can result in Russell-Silver syndrome (RSS). These two syndromes have numerous opposing phenotypes, especially with regards to growth parameters. The differences in the phenotype are proposed to be due to altered dosage of imprinted genes that control growth within this region of 11p15. Wolf-Hirschhorn syndrome (WHS) is due to deletions of a region in 4p16.3 and there is no known parent-of-origin effect for deletions of the WHS critical region, and no genes are known to be imprinted in this region. We report on three individuals with very similar unbalanced translocations resulting in a derivative chromosome 4 with both a deletion of 4p16.3 and a duplication of 11p15. Two of these individuals are family members with one inheriting the derivative 4 from her balanced mother and the other inheriting the derivative 4 from his balanced father. The third individual is unrelated and inherited his derivative 4 from his balanced father. While the findings of these individuals included some features of WHS and RSS or BWS, the phenotypes as an aggregate are distinct from these syndromes. The genomic and phenotypic characterization of these three individuals demonstrates how unbalanced translocations can result in the modification of chromosome duplication and deletion syndromes and identifies genomic architecture that may be responsible for mediating a recurrent translocation between 4p and 11p.