RESUMO
BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described. METHODS: Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition. RESULTS: We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery. CONCLUSIONS: Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.
Assuntos
Dissecção Aórtica , Fenótipo , Humanos , Masculino , Feminino , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Adulto , DNA Metiltransferase 3A , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Adolescente , Criança , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Mutação , Adulto Jovem , Aneurisma/genética , Aneurisma/patologia , Pré-EscolarRESUMO
BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
Assuntos
Anormalidades Múltiplas , Transtorno do Espectro Autista , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Anormalidades Dentárias , Masculino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Dentárias/genética , Fácies , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Proteínas Repressoras/genética , Deleção Cromossômica , Fenótipo , Fatores de Transcrição/genéticaRESUMO
PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype-phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype-phenotype correlations.
Assuntos
Distrofias Retinianas , Retinose Pigmentar , Humanos , Análise Mutacional de DNA , Mutação , Mutação de Sentido Incorreto , Fenótipo , Distrofias Retinianas/genética , Retinose Pigmentar/genéticaRESUMO
BACKGROUND: A proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS. METHODS: Employing an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant. RESULTS: Out of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases. CONCLUSIONS: The search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.
Assuntos
Síndrome de Marfan , Fibrilina-1/genética , Humanos , Síndrome de Marfan/patologia , Mosaicismo , MutaçãoRESUMO
TCF4 haploinsufficiency by deletions, truncating variants or loss-of-function missense variants within the DNA-binding and protein interacting bHLH domain causes Pitt-Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N-terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non-specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator-recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype-phenotype correlation for TCF4-related NDDs.
Assuntos
Epilepsia , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Fator de Transcrição 4/genética , Fácies , Hiperventilação/diagnósticoRESUMO
The PACS2 gene encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation that has been shown to be highly expressed during human prenatal brain development. Pathogenic variants in PACS2 have been recently shown to be implicated in a phenotype with global developmental delay/intellectual disability, seizures, autistic traits, facial dysmorphic features, and cerebellar dysgenesis. Here, we report a 25-year-old male with intellectual disability, epileptic encephalopathy, cerebellar dysgenesis, facial dysmorphism, and a previously reported pathogenic variant in PACS2. To our knowledge, this is the oldest patient reported who, in addition to the known phenotype described in PACS2 patients, presented with a vein of Galen malformation and dilated cardiomyopathy as previously unreported findings.
Assuntos
Aneurisma , Cardiomiopatia Dilatada , Doenças Cerebelares , Epilepsia Generalizada , Deficiência Intelectual , Malformações da Veia de Galeno , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Proteínas de Transporte Vesicular/genéticaRESUMO
Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.
Assuntos
Anormalidades do Olho , Lipomatose , Síndromes Neurocutâneas , Agenesia do Corpo Caloso , Fenda Labial , Coloboma , Anormalidades Craniofaciais , Diagnóstico Diferencial , Orelha Externa/anormalidades , Anormalidades do Olho/genética , Oftalmopatias , Face/anormalidades , Humanos , Lipoma , Lipomatose/genética , Pólipos Nasais , Síndromes Neurocutâneas/genética , Anormalidades do Sistema Respiratório , Dermatopatias , Coluna Vertebral/anormalidadesRESUMO
Rare diseases (RDs) as a whole affect a huge number of individuals although each specific condition comprises a low number of individuals. As a consequence, funds allocated to expand research to all conditions are often limited. Several initiatives have emerged to invest more resources for research in RDs, but patients express unmet needs regarding educational initiatives, awareness support, and psychosocial resources. We developed an educational training program in the format of weekly sessions covering basic medical scientific knowledge and psychosocial aspects of RDs. The aim of this initiative was to assess its overall impact regarding knowledge, psychological issues, and participant satisfaction. Items were evaluated through surveys before and after the sessions. Here, we report the experience and impact of two editions of this initiative with a total of 37 participants. Our results show improvements in knowledge and better management of the psychological impact. Moreover, participants were able to exchange experiences and concerns, most of which were shared even though the RDs were different. Overall, the program was evaluated by the participants as a highly beneficial experience and all of them were interested in attending advanced editions.
Assuntos
Doenças Raras , Escolaridade , Humanos , Inquéritos e QuestionáriosRESUMO
Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated.
Assuntos
Catarata/genética , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/genética , Anormalidades Musculoesqueléticas/genética , Proteínas Proto-Oncogênicas c-maf/genética , Adolescente , Adulto , Catarata/patologia , Criança , Pré-Escolar , Fácies , Feminino , Transtornos do Crescimento/patologia , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Anormalidades Musculoesqueléticas/patologia , Mutação de Sentido Incorreto/genética , Adulto JovemRESUMO
Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3' end of the gene, confirming the genotype-phenotype correlation initially described.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Espectro Autista/etiologia , Proteínas do Citoesqueleto/genética , Fatores de Transcrição/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/genética , Mutação com Perda de Função , Masculino , SíndromeRESUMO
Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene. Only 10 patients have been reported to date. We report two additional non related cases born to Moroccan consanguineous parents, carrying the previously described c.915_925dup11 CEP57 homozygous variant. Common features of these 12 cases include growth retardation, typically of prenatal onset, distinctive facial features, endocrine, cardiovascular and skeletal, abnormalities while malignancies have not been reported. This report describes the phenotypical spectrum of MVA2.
Assuntos
Transtornos Cromossômicos/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genética , Fenótipo , Criança , Transtornos Cromossômicos/patologia , Humanos , Masculino , Mosaicismo , MutaçãoRESUMO
Schuurs-Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50-74%), infrequent (26-49%) and rare (less than ≤25%).
Assuntos
Transtornos do Neurodesenvolvimento/genética , Proteínas de Transporte Vesicular/genética , Anormalidades Múltiplas/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Mutação/genética , Fenótipo , SíndromeRESUMO
BACKGROUND AND OBJECTIVE: Conventional cytogenetics diagnoses 3-5% of patients with unexplained developmental delay/intellectual disability and/or multiple congenital anomalies. The Multiplex Ligation-dependent Probe Amplification increases diagnostic rates from between 2.4 to 5.8%. Currently the comparative genomic hybridisation array or aCGH is the highest performing diagnostic tool in patients with developmental delay/intellectual disability, congenital anomalies and autism spectrum disorders. Our aim is to evaluate the efficiency of the use of aCGH as first-line test in these and other indications (epilepsy, short stature). PATIENTS AND METHOD: A total of 1000 patients referred due to one or more of the abovementioned disorders were analysed by aCGH. RESULTS: Pathogenic genomic imbalances were detected in 14% of the cases, with a variable distribution of diagnosis according to the phenotypes: 18.9% of patients with developmental delay/intellectual disability; 13.7% of multiple congenital anomalies, 9.76% of psychiatric pathologies, 7.02% of patients with epilepsy, and 13.3% of patients with short stature. Within the multiple congenital anomalies, central nervous system abnormalities and congenital heart diseases accounted for 14.9% and 10.6% of diagnoses, respectively. Among the psychiatric disorders, patients with autism spectrum disorders accounted for 8.9% of the diagnoses. CONCLUSIONS: Our results demonstrate the effectiveness and efficiency of the use of aCGH as the first line test in genetic diagnosis of patients suspected of genomic imbalances, supporting its inclusion within the National Health System.
Assuntos
Hibridização Genômica Comparativa/economia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/economia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/economia , Criança , Análise Custo-Benefício , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/genéticaRESUMO
We report on a new patient with a 7q terminal deletion. The 18-month-old boy had metal retardation, microcephaly, a distinctive face, bilateral coloboma, café-au-lait spot on the abdomen, and sacral agenesis. The high resolution GTG bands (550-850 bands), currently used in our laboratory, showed a 7q terminal deletion, which was also confirmed with fluorescence in situ hybridization (FISH). The homeobox HLXB9 gene, localized at 7q36 has been demonstrated to be involved in sacral agenesis; in fact patients with 7q terminal deletions frequently have this malformation. We could not perform molecular studies in this patient to confirm the HLXB9 haploinsufficiency, but we postulate that he carried it.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Meningomielocele/patologia , Sacro/anormalidades , Bandeamento Cromossômico , Humanos , Hibridização in Situ Fluorescente , Lactente , MasculinoAssuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Aneurisma da Aorta Torácica/etiologia , Diagnóstico Precoce , Síndrome de Loeys-Dietz/complicações , Síndrome de Marfan/complicações , Equipe de Assistência ao Paciente , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/prevenção & controle , Criança , Gerenciamento Clínico , Feminino , Testes Genéticos/métodos , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/terapia , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/terapia , PrognósticoRESUMO
A second family with the condition first described by Frías et al. in 1975 is presented. Those authors examined a mother and her son affected with short stature, facial anomalies (epicanthic folds, downward palpebral fissures, hyperthelorism, and eyelid ptosis), cup-shaped and posteriorly rotated ears, hand and foot defects, and delayed bone age. In the family we are presenting here, a girl, her mother, the mother's brother, and the propositus' maternal grandmother, were affected. This supports autosomal dominant inheritance, as proposed by (Frías et al. [1975] BDOAS 11:30-33), although with variable expressivity.
Assuntos
Anormalidades Múltiplas/patologia , Face/anormalidades , Deformidades Congênitas do Pé/patologia , Transtornos do Crescimento/patologia , Anormalidades Múltiplas/genética , Saúde da Família , Feminino , Genes Dominantes/genética , Humanos , Masculino , Linhagem , SíndromeRESUMO
In 1988 Pfeiffer and Kapferer reported on a patient with sensorineural deafness, psychomotor delay, hypospadias, cerebral manifestations, and bilateral synostosis of the 4th and 5th metacarpals and metatarsals. Synostosis of the 4th and 5th metacarpals and metatarsals is a very rare defect that has been described as an isolated Mendelian defect, as part of multiple congenital anomaly (MCA) patterns, and in different syndromes. Among a total of 2,023,155 liveborn infants in the Spanish Collaborative Study of Congenital Malformations (ECEMC), we observed only two cases with this type of metacarpal fusion, for a frequency of 1/1,011,577. One had the isolated defect, and the other one that we are describing here, had an MCA pattern similar to that described by Pfeiffer and Kapferer [1988]. We tested HOXD13 but did not find any mutations in exons and intron-exon boundaries. To our knowledge this case is the second one reported with this syndrome.
Assuntos
Anormalidades Múltiplas/patologia , Genitália Feminina/anormalidades , Perda Auditiva Neurossensorial/patologia , Deficiência Intelectual/patologia , Sinostose/patologia , Anormalidades Múltiplas/genética , Pré-Escolar , Análise Mutacional de DNA , Feminino , Proteínas de Homeodomínio/genética , Humanos , Lactente , Metacarpo/anormalidades , Ossos do Metatarso/anormalidades , Mutação , Síndrome , Fatores de Transcrição/genéticaRESUMO
The Wolf-Hirschhorn syndrome (WHS), is a well known contiguous gene syndrome characterized by microcephaly, hypertelorism, prominent glabella, epicanthal folds, cleft lip or palate, cardiac defects, growth and mental retardation and seizures. The currently accepted WHS critical region (WHSCR) is localized between the loci D4S166 and D4S3327, where a deletion seems to generate all the clinical manifestations of the syndrome. Here we present a patient with a subtelomeric deletion of 4p16.3 showing growth and psychomotor delay with a typical WHS facial appearance and two episodes of seizures in conjunction with fever. The high-resolution G-banded karyotype was normal. Fluorescence in situ hybridization (FISH) with a set of cosmids from 4p16.3, showed that the deletion in this patient was from the D4S3327 to the telomere, enabling the size of the deletion to be estimated as 1.9 Mb, excluding the accepted WHSCR deletion. This patient supports the recent proposal by Zollino et al. [2003] that the critical region for WHS is located distally to the WHSCR between the loci D4S3327 and D4S98-D4S16, and it is called "WHSCR-2" [Zollino et al., 2003].