Publications by authors named "Julia Baptista"

15 Publications

  • Page 1 of 1

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K channelopathies.

Eur J Hum Genet 2021 Feb 16. Epub 2021 Feb 16.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K conductance, referred to as syndromic neurodevelopmental K channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
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http://dx.doi.org/10.1038/s41431-021-00818-9DOI Listing
February 2021

Expanding the phenotypic spectrum of IFT81: Associated ciliopathy syndrome.

Am J Med Genet A 2020 10 11;182(10):2403-2408. Epub 2020 Aug 11.

Clinical Genetics Service, St Michael's hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Short-rib polydactyly syndromes are a heterogeneous group of disorders characterized by narrow thorax with short ribs, polydactyly and often other visceral and skeletal malformations. To date there have only been six reported patients with homozygous and compound heterozygous variants in IFT81, causing a short-rib thoracic dysplasia, with, or without, polydactyly (SRTD19: OMIM 617895). IFT81 is a protein integral to the core of the intraflagellar transport complex B (IFT-B), which is involved in anterograde transport in the cilium. We describe the case of a male infant with compound heterozygous variants in IFT81, who presented with short long bones, a narrow thorax, polydactyly, and multiple malformations. Three novel clinical features are reported including complete situs inversus, micropenis, and rectal atresia, which have not previously been associated with variants in IFT81. We reviewed the literature and identified the most consistent clinical features associated with this rare ciliopathy syndrome. We postulate that dolichocephaly and sagittal craniosynostosis may be associated with this condition, and provide a clue to considering IFT81 as the causative gene when deciphering complex ciliopathies.
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http://dx.doi.org/10.1002/ajmg.a.61781DOI Listing
October 2020

variants are associated with multiple congenital anomalies including ciliopathy phenotypes.

J Med Genet 2020 Jul 6. Epub 2020 Jul 6.

Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

Background: Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.

Methods: Among individuals from four unrelated families, we identified variants in ( that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted in frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of patient variants through rescue experiments in the frog model.

Results: Patients with variants of were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of in embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype in frog embryos depleted of introduction of patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.

Conclusion: These findings in both patient tissues and shed light on how mutations in may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.
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http://dx.doi.org/10.1136/jmedgenet-2019-106805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785698PMC
July 2020

Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor.

Front Mol Neurosci 2020 11;13:12. Epub 2020 Feb 11.

Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.

Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic microdeletion (Del-Ex37-38). missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals' has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.
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http://dx.doi.org/10.3389/fnmol.2020.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026477PMC
February 2020

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Am J Hum Genet 2020 02 30;106(2):272-279. Epub 2020 Jan 30.

Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX2 5DW, UK. Electronic address:

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010973PMC
February 2020

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

Hum Mutat 2020 02 3;41(2):403-411. Epub 2019 Dec 3.

Kids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia.

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.
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http://dx.doi.org/10.1002/humu.23938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306402PMC
February 2020

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

Compound heterozygous Pkd1l1 variants in a family with two fetuses affected by heterotaxy and complex Chd.

Eur J Med Genet 2020 Feb 23;63(2):103657. Epub 2019 Apr 23.

Department of Clinical Genetics, University Hospitals Bristol, Bristol, UK. Electronic address:

Heterotaxy and congenital heart defects associated with pathogenic variants in the PKD1L1 gene (autosomal visceral heterotaxy type 8, MIM 617205) has been reported in only four individuals from three unrelated families. We describe a further family with two affected fetuses and novel compound heterozygous pathogenic variants in PKD1L1. PKD1L1 has been shown to function in the ciliary sensation of nodal flow at the embryo primitive node and in the restriction of NODAL signalling to the left lateral. plate mesoderm, mechanisms involved in the development of laterality in vertebrates. Individuals affected with this autosomal recessive condition have variable thoracic and abdominal situs. Features of CHD and other anomalies vary between and within families.
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http://dx.doi.org/10.1016/j.ejmg.2019.04.014DOI Listing
February 2020

Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs.

Cell Stem Cell 2019 05 11;24(5):736-752.e12. Epub 2019 Apr 11.

Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria, Cantabria, Spain. Electronic address:

The pathological consequences of structural variants disrupting 3D genome organization can be difficult to elucidate in vivo due to differences in gene dosage sensitivity between mice and humans. This is illustrated by branchiooculofacial syndrome (BOFS), a rare congenital disorder caused by heterozygous mutations within TFAP2A, a neural crest regulator for which humans, but not mice, are haploinsufficient. Here, we present a BOFS patient carrying a heterozygous inversion with one breakpoint located within a topologically associating domain (TAD) containing enhancers essential for TFAP2A expression in human neural crest cells (hNCCs). Using patient-specific hiPSCs, we show that, although the inversion shuffles the TFAP2A hNCC enhancers with novel genes within the same TAD, this does not result in enhancer adoption. Instead, the inversion disconnects one TFAP2A allele from its cognate enhancers, leading to monoallelic and haploinsufficient TFAP2A expression in patient hNCCs. Our work illustrates the power of hiPSC differentiation to unveil long-range pathomechanisms.
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http://dx.doi.org/10.1016/j.stem.2019.03.004DOI Listing
May 2019

NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Brain 2019 01;142(1):50-58

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA USA.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.
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http://dx.doi.org/10.1093/brain/awy310DOI Listing
January 2019

Complete Genome Sequence of Bacillus velezensis LABIM40, an Effective Antagonist of Fungal Plant Pathogens.

Genome Announc 2018 Jun 21;6(25). Epub 2018 Jun 21.

Department of Microbiology, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil

strain LABIM40 holds high potential for biological control of plant pathogens. Its complete genome contains one chromosome of 3,972,310 bp with 3,777 DNA coding sequences and displays 33 gene clusters potentially involved in the suppression of fungal pathogens.
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http://dx.doi.org/10.1128/genomeA.00595-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013614PMC
June 2018

Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

Prenat Diagn 2018 01 3;38(1):33-43. Epub 2017 Dec 3.

Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

Objective: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred.

Method: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation.

Results: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum.

Conclusion: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/pd.5175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836855PMC
January 2018

De novo apparently balanced translocations in man are predominantly paternal in origin and associated with a significant increase in paternal age.

J Med Genet 2010 Feb 27;47(2):112-5. Epub 2009 Jul 27.

Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8TE, UK.

Background: Congenital chromosome abnormalities are relatively common in our species and among structural abnormalities the most common class is balanced reciprocal translocations. Determining the parental origin of de novo balanced translocations may provide insights into how and when they arise. While there is a general paternal bias in the origin of non-recurrent unbalanced rearrangements, there are few data on parental origin of non-recurrent balanced rearrangements.

Methods: The parental origin of a series of de novo balanced reciprocal translocations was determined using DNA from flow sorted derivative chromosomes and linkage analysis.

Results: Of 27 translocations, we found 26 to be of paternal origin and only one of maternal origin. We also found the paternally derived translocations to be associated with a significantly increased paternal age (p<0.008).

Conclusion: Our results suggest there is a very pronounced paternal bias in the origin of all non-recurrent reciprocal translocations and that they may arise during one of the numerous mitotic divisions that occur in the spermatogonial germ cells prior to meiosis.
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http://dx.doi.org/10.1136/jmg.2009.069716DOI Listing
February 2010

Breakpoint mapping and array CGH in translocations: comparison of a phenotypically normal and an abnormal cohort.

Am J Hum Genet 2008 Apr 27;82(4):927-36. Epub 2008 Mar 27.

Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, UK.

We report the analyses of breakpoints in 31 phenotypically normal and 14 abnormal carriers of balanced translocations. Our study assesses the differences between balanced translocations in normal carriers and those in abnormal carriers, focusing on the presence of genomic imbalances at the breakpoints or elsewhere in the genome, presence of cryptic chromosome rearrangements, and gene disruption. Our hypothesis is that all four features will be associated with phenotypic abnormalities and absent or much less frequent in a normal population. In the normal cohort, we identified neither genomic imbalances at the breakpoints or elsewhere in the genome nor cryptic chromosome rearrangements. In contrast, we identified candidate disease-causing imbalances in 4/14 abnormal patients. These were three breakpoint associated deletions and three deletions unrelated to the breakpoints. All six de novo deletions originated on the paternally inherited chromosome. Additional complexity was also present in one of these cases. Gene disruption by the breakpoints was present in 16/31 phenotypically normal individuals and in 5/14 phenotypically abnormal patients. Our results show that translocations in phenotypically abnormal patients are molecularly distinct from those in normal individuals: the former are more likely to be associated with genomic imbalances at the breakpoints or elsewhere and with chromosomal complexity, whereas the frequency of gene disruption is similar in both normal and abnormal translocation carriers.
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http://dx.doi.org/10.1016/j.ajhg.2008.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427237PMC
April 2008

Molecular cytogenetic analyses of breakpoints in apparently balanced reciprocal translocations carried by phenotypically normal individuals.

Eur J Hum Genet 2005 Nov;13(11):1205-12

Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, UK.

To test the hypothesis that translocation breakpoints in normal individuals are simple and do not disrupt genes, we characterised the breakpoints in 13 phenotypically normal individuals incidentally ascertained with an apparently balanced reciprocal translocation. Cases were karyotyped, and the breakpoints were refined by fluorescence in situ hybridisation until breakpoint-spanning clones were identified. 1 Mb array-CGH was performed as a whole genome analysis tool to detect any imbalances in chromatin not directly involved in the breakpoints. Breakpoint-associated imbalances were not found in any of the patients analysed in this study. However, breakpoints which disrupted known genes were identified in two patients, with RYR2 disrupted in one patient and COL13A1 in the other. In a further eight patients, Ensembl mapping data suggested that a gene might be disrupted by a breakpoint. In one further patient, the translocation was shown to be nonreciprocal. This study shows that apparently balanced reciprocal translocations in phenotypically normal patients do not have imbalances at the breakpoints, in contrast to phenotypically abnormal patients where the translocation breakpoints are often associated with cryptic imbalances. However, phenotypically normal individuals, and phenotypically abnormal individuals may have genes disrupted and therefore inactivated by one of the breakpoints. The significance of these disruptions remains to be determined.
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http://dx.doi.org/10.1038/sj.ejhg.5201488DOI Listing
November 2005