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The severe end of the spectrum: Hypoplastic left heart in Potocki-Lupski syndrome.

ABSTRACT: Potocki-Lupski syndrome (PTLS) is a recently described microduplication syndrome associated with duplication 17p11.2, including the RAI1 gene. Features of PTLS include hypotonia, feeding difficulties, failure to thrive, developmental delay and behavioral abnormalities including autistic spectrum disorder, anxiety, and inattention. Cardiovascular anomalies were not recognized as a feature of duplication 17p11.2 until 2007 when noted in over 50% of a clinically characterized cohort. We report a patient with hypoplastic left heart syndrome whose diagnosis of PTLS was delayed until a genetic evaluation at age 4 years because of severe expressive language impairment. We suggest that array comparative genomic hybridization be performed in infants with severe congenital heart defects.

SUBMITTER: Sanchez-Valle A

PROVIDER: S-EPMC3092288 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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The severe end of the spectrum: Hypoplastic left heart in Potocki-Lupski syndrome.

Sanchez-Valle Amarilis A Pierpont Mary Ella ME Potocki Lorraine L

American journal of medical genetics. Part A 20110113 2

Potocki-Lupski syndrome (PTLS) is a recently described microduplication syndrome associated with duplication 17p11.2, including the RAI1 gene. Features of PTLS include hypotonia, feeding difficulties, failure to thrive, developmental delay and behavioral abnormalities including autistic spectrum disorder, anxiety, and inattention. Cardiovascular anomalies were not recognized as a feature of duplication 17p11.2 until 2007 when noted in over 50% of a clinically characterized cohort. We report a pa ...[more]

PMID: 21271655

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Family case of Potocki-Lupski syndrome.

Project description:BackgroundPotocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging.Case presentationWe report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region.ConclusionsChildren with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.

| S-EPMC10960457 | biostudies-literature

Does the Potocki-Lupski Syndrome Convey the Autism Spectrum Disorder Phenotype? Case Report and Scoping Review.

Project description:Potocki-Lupski Syndrome (PTLS) is a rare condition associated with a duplication of 17p11.2 that may underlie a wide range of congenital abnormalities and heterogeneous behavioral phenotypes. Along with developmental delay and intellectual disability, autism-specific traits are often reported to be the most common among patients with PTLS. To contribute to the discussion of the role of autism spectrum disorder (ASD) in the PTLS phenotype, we present a case of a female adolescent with a de novo dup(17) (p11.2p11.2) without ASD features, focusing on in-depth clinical, behavioral, and electrophysiological (EEG) evaluations. Among EEG features, we found the atypical peak-slow wave patterns and a unique saw-like sharp wave of 13 Hz that was not previously described in any other patient. The power spectral density of the resting state EEG was typical in our patient with only the values of non-linear EEG dynamics: Hjorth complexity and fractal dimension were drastically attenuated compared with the patient's neurotypical peers. Here we also summarize results from previously published reports of PTLS that point to the approximately 21% occurrence of ASD in PTLS that might be biased, taking into account methodological limitations. More consistent among PTLS patients were intellectual disability and speech and language disorders.

| S-EPMC10053863 | biostudies-literature

The complex genetics of hypoplastic left heart syndrome.

Project description:Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR-Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD.

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Micro-RNA expression in hypoplastic left heart syndrome.

Project description:ObjectiveMicro-RNAs (miRNAs) are important regulators of gene expression through interaction with the 3'UTR of target messenger RNAs (mRNAs). The role of miRNAs has been extensively studied in adult human and nonhuman animal models of heart disease. Hypoplastic left heart syndrome (HLHS) is the most common form of severe congenital heart disease and is an important cause of morbidity and mortality in infants and children. The objective of this work was to analyze the miRNA profile in HLHS patients.Methods and resultsmiRNA profile was determined in the right ventricle with the use of miRNA array, and expression was validated with the use of reverse-transcription polymerase chain reaction (RT-PCR). Based on bioinformatics analysis, targets were selected and their expression analyzed with the use of RT-PCR.We found that the miRNA profile of HLHS is novel, with few similarities between pediatric and adult idiopathic dilated cardiomyopathy. Moreover, our analysis identified putative targets for these miRNAs that are known to be important for cardiac development and disease, and that miRNAs and their putative targets are antithetically regulated. We also found that miRNA expression changes with stage of surgery, suggesting that volume unloading of the ventricle has important consequences for gene expression.ConclusionsOur data suggest a unique miRNA profile for HLHS that may be associated with defects in cardiac development and disease.

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Objective measures of sleep disturbances in children with Potocki-Lupski syndrome.

Project description:Potocki-Lupski syndrome (PTLS; MIM 610883) is a neurodevelopmental disorder caused by a microduplication, a 3.7 Mb copy number variant, mapping within chromosome 17p11.2, encompassing the dosage-sensitive RAI1 gene. Whereas RAI1 triplosensitivity causes PTLS, haploinsufficiency of RAI1 due to 17p11.2 microdeletion causes the clinically distinct Smith-Magenis syndrome (SMS; MIM 182290). Most individuals with SMS have an inversion of the melatonin cycle. Subjects with PTLS have mild sleep disturbances such as sleep apnea with no melatonin abnormalities described. Sleep patterns and potential disturbances in subjects with PTLS have not been objectively characterized. We delineated sleep characteristics in 23 subjects with PTLS who underwent a polysomnogram at Texas Children's Hospital. Eleven of these subjects (58%) completed the Child's Sleep Habits Questionnaire (CSHQ). Urinary melatonin was measured in one patient and published previously. While the circadian rhythm of melatonin in PTLS appears not to be disrupted, we identified significant differences in sleep efficiency, percentage of rapid eye movement sleep, oxygen nadir, obstructive apnea hypopnea index, and periodic limb movements between prepubertal subjects with PTLS and previously published normative data. Data from the CSHQ indicate that 64% (7/11) of parents do not identify a sleep disturbance in their children. Our data indicate that younger individuals, <10 years, with PTLS have statistically significant abnormalities in five components of sleep despite lack of recognition of substantial sleep disturbances by parents. Our data support the contention that patients with PTLS should undergo clinical evaluations for sleep disordered breathing and periodic limb movement disorder, both of which are treatable conditions.

| S-EPMC6953247 | biostudies-literature

Impact of MYH6 variants in hypoplastic left heart syndrome.

Project description:Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10-5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10-2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10-3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10-2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications.

| S-EPMC5206387 | biostudies-literature

Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome.

Project description:Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by abnormalities in the left ventricle, associated valves, and ascending aorta. Studies have shown intrinsic myocardial defects but do not sufficiently explain developmental defects in the endocardial-derived cardiac valve, septum, and vasculature. Here, we identify a developmentally impaired endocardial population in HLHS through single-cell RNA profiling of hiPSC-derived endocardium and human fetal heart tissue with an underdeveloped left ventricle. Intrinsic endocardial defects contribute to abnormal endothelial-to-mesenchymal transition, NOTCH signaling, and extracellular matrix organization, key factors in valve formation. Endocardial abnormalities cause reduced cardiomyocyte proliferation and maturation by disrupting fibronectin-integrin signaling, consistent with recently described de novo HLHS mutations associated with abnormal endocardial gene and fibronectin regulation. Together, these results reveal a critical role for endocardium in HLHS etiology and provide a rationale for considering endocardial function in regenerative strategies.

| S-EPMC7541479 | biostudies-literature

Potocki-Lupski syndrome: a microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive.

Project description:ObjectiveFailure to thrive (FTT) is a feature of children with Potocki-Lupski syndrome (PTLS) [duplication 17p11.2]. This study was designed to describe the growth characteristics of 24 subjects with PTLS from birth through age 5 years in conjunction with relevant physical features and swallow function studies.Study designWe evaluated 24 individuals with PTLS who were ascertained by chromosome analysis and/or array comparative genome hybridization. Clinical assessments included review of medical records, physical examination, otolaryngological examination, and swallow function studies. Measures of height and weight were converted to Z-scores.ResultsThe mean weight-for-age and weight-for-length Z-scores at birth were lower (P < .01) than the reference standard and did not change with age. A history of poor feeding, hypotonia, and FTT were reported in 92%, 88%, and 71%, respectively. Individuals with hypotonia had lower weight-for-age and body mass index-for-age Z-scores (P = .01). Swallow function studies demonstrated at least one abnormality in all subjects.ConclusionsFTT is common in children with PTLS. We hypothesize that oropharyngeal dysphagia and hypotonia likely contribute to FTT in patients with PTLS and recommend that once a diagnosis is established, the individual be assessed for feeding and growth issues and be availed of oromotor therapy and nutritional services.

| S-EPMC3059370 | biostudies-literature

Hypoplastic Left Heart Syndrome Single Cell RNA Sequencing

Project description:Single cell transcriptome analysis was performed on one Hypoplastic Left Heart Synrome (HLHS) cell line and one control cell line.

2020-03-11 | GSE146763 | GEO

The complex genetics of hypoplastic left heart syndrome

Project description:Congenital heart disease (CHD) is a prevalent birth defect affecting up to 1% of live births. While a genetic etiology is indicated by increased recurrence risk and association with chromosomal abnormalities, the genetics of CHD is poorly understood and likely complex. Here we show hypoplastic left heart syndrome (HLHS), a severe CHD with high morbidity/mortality, has a multigenic etiology. Analysis of 8 HLHS mutant mouse lines recovered from a large-scale mutagenesis screen showed no mutations are shared in common. In the *Ohia* mouse line, mutations in 2 genes, *Pcdha9*/*Sap130*, act synergistically to cause HLHS. Cardiomyocyte proliferation and differentiation defects likely act in concert with valve abnormalities to cause HLHS. Network analysis of mutations recovered in HLHS mice and 68 HLHS patients point to Notch signaling disruption, a pathway previously implicated in HLHS. These findings demonstrate large-scale mutagenesis is an effective systems approach for interrogating the complex genetics of human diseases. SUBMITTER_CITATION: Journal: Nature Genetics Title: The complex genetics of hypoplastic left heart syndrome Author names: Xiaoqin Liu1, Hisato Yagi1, Shazina Saeed1, Abha S. Bais1, George C. Gabriel1, Zhaohan Chen1, Kevin A. Peterson4, You Li1, Molly C. Schwartz1, William T. Reynolds1, Manush Saydmohammed1, Brian Gibbs1, Yijen Wu1, William Devine1, Bishwanath Chatterjee1, Nikolai T. Klena1, Dennis Kostka1, Karen L. de Mesy Bentley5, Madhavi K.Ganapathiraju2, Phillip Dexheimer11, Linda Leatherbury7, Omar Khalifa1, Anchit Bhagat1, Maliha Zahid1, William Pu8, Simon Watkins3, Paul Grossfeld9, Stephen Murray4, George A. Porter, Jr.6, Michael Tsang1, Lisa J.Martin10, D.Woodrow.Benson12, Bruce J. Aronow11, Cecilia W. Lo1

2017-04-13 | GSE77799 | GEO

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