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1.
Am J Hum Genet ; 105(2): 283-301, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353023

RESUMO

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

2.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
4.
Am J Hum Genet ; 103(5): 786-793, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343942

RESUMO

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.

5.
Eur J Hum Genet ; 26(11): 1623-1634, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29925855

RESUMO

We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca2+ release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca2+ release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.

6.
J Pediatr ; 186: 196-199, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28456387

RESUMO

In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01913340.


Assuntos
Lesões Encefálicas/diagnóstico por imagem , Eritropoetina/uso terapêutico , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Imagem por Ressonância Magnética , Fármacos Neuroprotetores/uso terapêutico , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Método Duplo-Cego , Feminino , Humanos , Hipóxia-Isquemia Encefálica/patologia , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
7.
Ophthalmic Genet ; 38(6): 570-574, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28481155

RESUMO

INTRODUCTION: Autosomal recessive bestrophinopathy (ARB) is a retinal disease caused by biallelic mutations of the BEST1 gene. It has a variable phenotype with white flecks in the retina, multifocal yellow subretinal deposits, macular edema, choroidal neovascularization, hyperopia, and electrophysiological abnormalities. We describe a family with ARB and multigenerational inheritance. METHODS: Three generations of a Middle Eastern family (a woman, one son, and two grandchildren) were evaluated by our ocular genetics team. Eye examinations, fundus photography, and optical coherence tomography (OCT) were performed. Genetic testing was obtained on examined patients and available relatives. RESULTS: The proband demonstrated counting fingers vision and white flecks in the retinal periphery, with macular subretinal fluid (SRF), loss of outer photoreceptor segments, and epiretinal membrane (ERM) on OCT. Two grandchildren demonstrated decreased vision, multifocal yellow subretinal deposits, and SRF on OCT. Two grandchildren examined elsewhere were reported to be similarly affected. A son's examination was normal except for extra-macular scars (from prior toxoplasmosis) and ERM. Genetic history revealed consanguinity and testing showed homozygosity for BEST1 mutations in the proband and two grandchildren c.473G>A/c.473G>A (R218H /R218H) and heterozygosity in two unaffected sons and two unaffected daughters-in-law c.473G>A/WT (p.R218H/WT). DISCUSSION: We present a consanguineous family of five affected individuals with ARB and four confirmed carriers. Their pedigree was consistent with dominant inheritance and incomplete penetrance. Genetic testing clarified the diagnosis and mode of inheritance. We describe the genetic findings, phenotypic variability, and recessive inheritance of an often dominantly inherited mutation as notable elements in their case.


Assuntos
Bestrofinas/genética , Oftalmopatias Hereditárias/genética , Padrões de Herança , Mutação , Doenças Retinianas/genética , Adulto , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Feminino , Genes Recessivos , Estudos de Associação Genética , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Doenças Retinianas/diagnóstico , Tomografia de Coerência Óptica
8.
Int J Mol Sci ; 17(9)2016 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-27657040

RESUMO

The author wishes to make a change to the published paper [1].[...].

9.
Clin Case Rep ; 4(7): 696-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27386132

RESUMO

Rubinstein-Taybi syndrome is associated with intellectual and physical features. CREBBP and EP300 are causative. Few cases of EP300 mutations are reported. We report a case with mild features of RSTS and EP300 mutation on exome sequencing. This illustrates the utility of exome sequencing to expand every genetic phenotype.

10.
Mol Genet Genomic Med ; 4(4): 465-74, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27441201

RESUMO

BACKGROUND: Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, encoding a neuromuscular specific translation elongation factor, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation, of which five are newly described. METHODS: New cases were identified and sequenced through the Deciphering Developmental Disabilities project, via direct contact with neurologists or geneticists, or recruited via our website. RESULTS: All the mutations cause epilepsy and intellectual disability, but with a much wider range of severity than previously identified. All new cases share specific subtle facial dysmorphic features. Each mutation occurs at an evolutionarily highly conserved amino acid position indicating strong structural or functional selective pressure. CONCLUSIONS: EEF1A2 should be considered as a causative gene not only in cases of epileptic encephalopathy but also in children with less severe epilepsy and intellectual disability. The emergence of a possible discernible phenotype, a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth may help in identifying patients with mutations in EEF1A2.

12.
Cold Spring Harb Mol Case Stud ; 2(1): a000661, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27148580

RESUMO

We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore-microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.

14.
Neurogenetics ; 17(3): 159-64, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27003583

RESUMO

Human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay.


Assuntos
Transtornos Dismórficos Corporais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Adolescente , Transtornos Dismórficos Corporais/complicações , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação , Sequenciamento Completo do Exoma
15.
Int J Mol Sci ; 17(2)2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26840296

RESUMO

Early presumptions opined that autism spectrum disorder (ASD) was related to the rearing of these children by emotionally-distant mothers. Advances in the 1960s and 1970s clearly demonstrated the biologic basis of autism with a high heritability. Recent advances have demonstrated that specific etiologic factors in autism spectrum disorders can be identified in 30%-40% of cases. Based on early reports newer, emerging genomic technologies are likely to increase this diagnostic yield to over 50%. To date these investigations have focused on etiologic factors that are largely mono-factorial. The currently undiagnosed causes of ASDs will likely be found to have causes that are more complex. Epigenetic, multiple interacting loci, and four dimensional causes (with timing as a variable) are likely to be associated with the currently unidentifiable cases. Today, the "Why" is more important than ever. Understanding the causes of ASDs help inform families of important issues such as recurrence risk, prognosis, natural history, and predicting associated co-morbid medical conditions. In the current era of emerging efforts in "personalized medicine", identifying an etiology will be critical in identifying endo-phenotypic groups and individual variations that will allow for tailored treatment for persons with ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Testes Genéticos , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Epigênese Genética , Humanos
16.
J Med Genet ; 53(5): 330-7, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26769062

RESUMO

BACKGROUND: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome. METHODS: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function. RESULTS: We identified a single heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in transducin ß-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome. CONCLUSIONS: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.


Assuntos
Expressão Gênica , Lipomatose/metabolismo , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Adulto , Criança , Análise Mutacional de DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Facies , Feminino , Humanos , Lipomatose/genética , Lipomatose/patologia , Masculino , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Correpressor 1 de Receptor Nuclear/metabolismo , Especificidade de Órgãos , Estrutura Terciária de Proteína , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Adulto Jovem
17.
Eur J Hum Genet ; 24(7): 1080-3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26577041

RESUMO

Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.


Assuntos
Proteínas de Transporte/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hemizigoto , Distúrbios do Metabolismo do Ferro/genética , Distrofias Neuroaxonais/genética , Adolescente , Adulto , Cromossomos Humanos X/genética , Exoma , Feminino , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/patologia , Masculino , Mosaicismo , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/patologia , Linhagem , Adulto Jovem
18.
Cytogenet Genome Res ; 147(1): 31-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26571231

RESUMO

Sex chromosome aneuploidies range in incidence from rather common to exceedingly rare and have a variable phenotype. We report 2 patients with sex chromosome aneuploidies who developed severe aplastic anemia requiring treatment. The first patient had tetrasomy X (48,XXXX) and presented at 9 years of age, and the second patient had trisomy X (47,XXX) and presented at 5 years of age. Although aplastic anemia has been associated with other chromosomal abnormalities, sex chromosome abnormalities have not been traditionally considered a risk factor for this condition. A review of the literature reveals that at least one other patient with a sex chromosome aneuploidy (45,X) has suffered from aplastic anemia and that other autosomal chromosomal anomalies have been described. Despite the uncommon nature of each condition, it is possible that the apparent association is coincidental. A better understanding of the genetic causes of aplastic anemia remains important.


Assuntos
Anemia Aplástica/genética , Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Infecções Oportunistas/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Adolescente , Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Transplante de Medula Óssea , Pré-Escolar , Cromossomos Humanos X/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/terapia , Feminino , Sobrevivência de Enxerto , Humanos , Deficiência Intelectual/imunologia , Deficiência Intelectual/patologia , Deficiência Intelectual/terapia , Cariotipagem , Infecções Oportunistas/imunologia , Infecções Oportunistas/patologia , Infecções Oportunistas/terapia , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/patologia , Resultado do Tratamento , Trissomia/patologia
19.
Am J Med Genet A ; 167A(12): 2893-901, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26420300

RESUMO

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.


Assuntos
Criptorquidismo/etiologia , Criptorquidismo/terapia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/terapia , Deformidades Congênitas da Mão/etiologia , Deformidades Congênitas da Mão/terapia , Cardiopatias/cirurgia , Deficiência Intelectual/etiologia , Deficiência Intelectual/terapia , Criança , Criptorquidismo/complicações , Eletrocardiografia , Facies , Feminino , Transtornos do Crescimento/complicações , Deformidades Congênitas da Mão/complicações , Transplante de Coração , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação , Gravidez , Proteína Smad4/genética , Adulto Jovem
20.
Am J Med Genet A ; 167A(9): 2168-75, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25914130

RESUMO

The coexistence of two or more distinct genetic conditions is known to be a rare phenomenon. Full chromosome aneuploidies can be associated with a broad variety of cytogenetic abnormalities or single gene disorders resulting in phenotypic modifications that confuse the diagnostic process. We present six patients with primary aneuploidies and a suspected or confirmed secondary genetic diagnosis or unusual birth defect. Among the cases included, we report the first patients with concurrent Down syndrome in combination with Prader-Willi, Craniofacial Microsomia, and Stickler syndromes. We also describe only the second reported case of a neonate with Down syndrome and Marfan syndrome. In all cases, the unusual clinical presentations lead to further molecular cytogenetic studies as well as single or multi-gene molecular evaluations. We make emphasis on the importance of entertaining the possibility of coexistent diagnoses when the phenotype is not what is expected for aneuploidies rather than attributing the unusual findings to rare or unreported associations of the primary aneuploidy.


Assuntos
Transtornos Cromossômicos/genética , Anormalidades Congênitas/genética , Doenças Genéticas Inatas/genética , Aneuploidia , Criança , Pré-Escolar , Aberrações Cromossômicas , Comorbidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo
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