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1.
Am J Hum Genet ; 109(2): 361-372, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35051358

RESUMEN

Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.


Asunto(s)
Proteína BRCA1/genética , Mutación de Línea Germinal , Mutación con Pérdida de Función , Mutación Missense , Trastornos del Neurodesarrollo/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Adolescente , Proteína BRCA1/inmunología , Niño , Preescolar , Cromatina/química , Cromatina/inmunología , Ensamble y Desensamble de Cromatina/genética , Ensamble y Desensamble de Cromatina/inmunología , Familia , Femenino , Regulación de la Expresión Génica , Heterocigoto , Histonas/genética , Histonas/inmunología , Factor C1 de la Célula Huésped/genética , Factor C1 de la Célula Huésped/inmunología , Humanos , Lactante , Masculino , Trastornos del Neurodesarrollo/inmunología , Trastornos del Neurodesarrollo/patología , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/inmunología , Ubiquitina/genética , Ubiquitina/inmunología , Ubiquitina Tiolesterasa/deficiencia , Ubiquitina Tiolesterasa/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitinación
2.
J Med Genet ; 61(6): 503-519, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38471765

RESUMEN

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.


Asunto(s)
Proteína de Unión a CREB , Proteína p300 Asociada a E1A , Síndrome de Rubinstein-Taybi , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/terapia , Humanos , Proteína de Unión a CREB/genética , Proteína p300 Asociada a E1A/genética , Consenso , Manejo de la Enfermedad , Mutación
3.
Am J Hum Genet ; 108(1): 8-15, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33417889

RESUMEN

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.


Asunto(s)
Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Genómica/métodos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Genotipo , Humanos , Mutación/genética , Fenotipo
4.
Prenat Diagn ; 44(2): 237-246, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37632214

RESUMEN

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.


Asunto(s)
Enfermedades Renales Quísticas , Enfermedades Renales , Anomalías Urogenitales , Reflujo Vesicoureteral , Embarazo , Femenino , Humanos , Deleción Cromosómica , Riñón/diagnóstico por imagen , Riñón/anomalías , Enfermedades Renales/congénito , Fenotipo , Enfermedades Renales Quísticas/diagnóstico por imagen , Enfermedades Renales Quísticas/genética , Factor Nuclear 1-beta del Hepatocito/genética , Estudios Multicéntricos como Asunto
5.
Brain ; 144(7): 2092-2106, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-33704440

RESUMEN

T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.


Asunto(s)
Canales de Calcio/genética , Canales de Calcio/metabolismo , Activación del Canal Iónico/genética , Trastornos del Neurodesarrollo/genética , Adulto , Animales , Encéfalo/metabolismo , Encéfalo/patología , Niño , Simulación por Computador , Femenino , Mutación con Ganancia de Función , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Modelos Moleculares , Modelos Neurológicos , Mutación Missense , Neuronas/metabolismo , Linaje , Conformación Proteica
6.
Am J Med Genet A ; 185(6): 1649-1665, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33783954

RESUMEN

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.


Asunto(s)
Predisposición Genética a la Enfermedad , Trastornos del Crecimiento/genética , N-Metiltransferasa de Histona-Lisina/genética , Hipertricosis/congénito , Discapacidad Intelectual/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Población Negra/genética , Estreñimiento/epidemiología , Estreñimiento/genética , Estreñimiento/patología , Insuficiencia de Crecimiento/epidemiología , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Estudios de Asociación Genética , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/patología , Humanos , Hipertricosis/epidemiología , Hipertricosis/genética , Hipertricosis/patología , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/patología , Mutación con Pérdida de Función/genética , Estudios Retrospectivos , Población Blanca/genética
7.
Am J Med Genet A ; 182(4): 623-627, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32003537

RESUMEN

Rhombencephalosynapsis (RES) is a rare congenital anomaly of the hindbrain characterized by fusion of the cerebellar hemispheres, cerebellar peduncles, and dentate nuclei with vermian absence or hypogenesis. This anomaly can be isolated or part of a larger spectrum of cerebral abnormalities. At least 90 cases are described in the literature and it has been associated with VACTERL and Gomez-Lopez-Hernandez syndrome (GLHS). The most common congenital syndrome associated with RES is GLHS, a rare presumed genetic disorder with over 30 cases thus far described in the literature. No genetic cause has been identified for RES or GLHS. We report two probands diagnosed with GLHS based on clinical criteria. Each proband had RES and bi-parietal scalp alopecia as well as neurologic findings and phenotypic features including trigeminal anesthesia, borderline hypertelorism, midface retrusion, and motor delay. Oliginucleotide-SNP microarray on the male proband revealed a 1.05 Mb copy duplication of uncertain clinical significance at 15q21.3 while oligonucleotide-SNP microarray for the female proband did not reveal any abnormalities. Exome sequencing (ES) was performed on both patients and did not identify any variants that could explain the GLHS phenotype. To our knowledge, these are the first two patients with GLHS described in the literature to undergo ES. Both patients had mild neurologic manifestations requiring physical therapy in early life without known diagnostic cause. Patients found to have scalp alopecia or trigeminal anesthesia with gross motor delay should be evaluated for RES or GLHS as well as screened for associated syndromes and have a complete neurodevelopmental evaluation.


Asunto(s)
Anomalías Múltiples/patología , Alopecia/patología , Cerebelo/anomalías , Anomalías Craneofaciales/patología , Exoma/genética , Trastornos del Crecimiento/patología , Síndromes Neurocutáneos/patología , Rombencéfalo/patología , Anomalías Múltiples/genética , Adolescente , Alopecia/genética , Cerebelo/patología , Anomalías Craneofaciales/genética , Femenino , Trastornos del Crecimiento/genética , Humanos , Masculino , Síndromes Neurocutáneos/genética , Fenotipo , Rombencéfalo/anomalías , Secuenciación del Exoma
8.
J Pediatr Hematol Oncol ; 42(4): e228-e230, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-30951021

RESUMEN

Phosphoglycerate kinase (PGK) is glycolytic enzyme critical in the creation of adenosine triphosphate. Mutations in the gene for this enzyme, PGK1, are associated with PGK deficiency, which is characterized by neurologic symptoms, nonhereditary spherocytic hemolytic anemia, and myopathy. We present a 20-year-old male with a novel c.461T>C (p.L154P) PGK1 mutation and clinical disease complicated by anemia and neurological symptoms. There is no recommended treatment for PGK deficiency. Because of our patient's advanced disease progression, we initiated serial blood transfusions and report significant subjective improvement in the patient's physical condition before his passing from PGK deficiency-related complications.


Asunto(s)
Transfusión Sanguínea , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Fosfoglicerato Quinasa/deficiencia , Mutación Puntual , Adulto , Humanos , Masculino , Fosfoglicerato Quinasa/genética
10.
Genet Med ; 21(10): 2199-2207, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30894705

RESUMEN

PURPOSE: We evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF). METHODS: Results of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated. RESULTS: Among patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic. CONCLUSION: Patients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.


Asunto(s)
Técnicas y Procedimientos Diagnósticos/estadística & datos numéricos , Secuenciación del Exoma/métodos , Pruebas Genéticas/métodos , Diagnóstico Diferencial , Exoma/genética , Femenino , Genómica/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Mutación/genética , Fenotipo , Estudios Retrospectivos , Análisis de Secuencia de ADN/métodos
11.
Am J Med Genet A ; 179(8): 1543-1546, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31207089

RESUMEN

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.


Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Hipoxia-Isquemia Encefálica/diagnóstico , Fenotipo , Distrés Psicológico , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , Masculino , Embarazo
12.
Am J Hum Genet ; 96(3): 462-73, 2015 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-25683120

RESUMEN

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).


Asunto(s)
Contractura/genética , Extremidades/fisiopatología , Cara/anomalías , Hipotonía Muscular/genética , Canales de Sodio/genética , Artrogriposis/genética , Disostosis Craneofacial/genética , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Exoma , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Lactante , Canales Iónicos , Masculino , Proteínas de la Membrana , Mutación Missense , Canales de Sodio/metabolismo
13.
Am J Hum Genet ; 97(1): 99-110, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26119818

RESUMEN

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.


Asunto(s)
Anomalías Múltiples/genética , Anomalías del Ojo/genética , Enfermedades de los Párpados/genética , Hirsutismo/genética , Hipertelorismo/genética , Hipertricosis/genética , Macrostomía/genética , Modelos Moleculares , Fenotipo , Proteínas Represoras/genética , Anomalías Cutáneas/genética , Proteína 1 Relacionada con Twist/genética , Anomalías Múltiples/patología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Inmunoprecipitación de Cromatina , Exoma/genética , Anomalías del Ojo/patología , Enfermedades de los Párpados/patología , Células HeLa , Hirsutismo/patología , Humanos , Hipertelorismo/patología , Hipertricosis/patología , Macrostomía/patología , Microscopía Electrónica , Datos de Secuencia Molecular , Mutación Missense/genética , Conformación Proteica , Proteínas Represoras/química , Análisis de Secuencia de ADN , Anomalías Cutáneas/patología , Proteína 1 Relacionada con Twist/química , Pez Cebra
14.
Am J Med Genet A ; : 1463-1536, 2018 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-29696775

RESUMEN

The 38th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on August 26th - 29th, 2017 at the Stoweflake Resort and Conference Center in Stowe, VT. The Workshop, which honors the legacy of David W Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted four themes besides mechanisms of morphogenesis and new syndromes: Disorders of Transcriptional Regulation, Dysmorphology (Syndromes and Malformations) in Minority and Unique Populations, Syndromes and Isolated Birth Defects Involving Malformations of the Developing Foregut, and the Natural History of Syndromes. This Conference Report includes the abstracts presented at the 2017 Workshop.

15.
Am J Med Genet A ; 176(11): 2243-2249, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30276953

RESUMEN

Congenital lumbar hernia is a rare anomaly consisting of protrusion of abdominal organs or extraperitoneal tissue through a defect in the lateral abdominal wall. The majority of affected patients have additional anomalies in a pattern described as the lumbocostovertebral syndrome. We report four patients born to mothers with poorly controlled diabetes with congenital lumbar hernia. All patients exhibited features of lumbocostovertebral syndrome with lumbar hernia, multiple vertebral segmentation anomalies in the lower thoracic and/or upper lumbar spine, rib anomalies, and unilateral renal agenesis. Additional anomalies present in the patients included preaxial hallucal polydactyly, abnormal situs, and sacral dysgenesis, anomalies known to be associated with diabetic embryopathy. At least 11 other patients have been previously reported with the lumbocostovertebral syndrome in the setting of maternal diabetes. We suggest that congenital lumbar hernia and the lumbocostovertebral syndrome are related to diabetic embryopathy.


Asunto(s)
Diabetes Gestacional/patología , Enfermedades Fetales/patología , Hernia/congénito , Hernia/complicaciones , Vértebras Lumbares/anomalías , Adulto , Preescolar , Femenino , Enfermedades Fetales/diagnóstico por imagen , Hernia/diagnóstico por imagen , Humanos , Recién Nacido , Vértebras Lumbares/diagnóstico por imagen , Masculino , Embarazo
16.
Am J Med Genet A ; 167A(10): 2399-401, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26097216

RESUMEN

Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome which may include malformations of the central nervous system, heart, genitourinary tract, and other organs. However, intestinal malrotation has not been previously known to be associated with RSTS. This report documents six persons with RSTS who also had malrotation of the intestine requiring surgical repair. This suggests a possible increased frequency of malrotation in RSTS. Diagnostic studies for malrotation should be considered if recurrent vomiting, abdominal pain, and other symptoms of possible malrotation are present.


Asunto(s)
Anomalías del Sistema Digestivo/patología , Vólvulo Intestinal/patología , Intestinos/patología , Síndrome de Rubinstein-Taybi/patología , Anomalías del Sistema Digestivo/diagnóstico , Anomalías del Sistema Digestivo/diagnóstico por imagen , Anomalías del Sistema Digestivo/cirugía , Femenino , Humanos , Lactante , Recién Nacido , Vólvulo Intestinal/diagnóstico , Vólvulo Intestinal/diagnóstico por imagen , Vólvulo Intestinal/cirugía , Intestinos/cirugía , Masculino , Radiografía , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/diagnóstico por imagen , Síndrome de Rubinstein-Taybi/cirugía
17.
Am J Hum Genet ; 89(1): 28-43, 2011 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-21700266

RESUMEN

We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.


Asunto(s)
Acetiltransferasas/deficiencia , Acetiltransferasas/genética , Cromosomas Humanos X/genética , Genes Ligados a X , Acetilación , Exones , Haplotipos , Humanos , Recién Nacido , Masculino , Mutación , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Linaje , Fenotipo
18.
J Med Genet ; 50(3): 194-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23355746

RESUMEN

BACKGROUND: Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies. METHODS: The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients. RESULTS: Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation. CONCLUSIONS: To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.


Asunto(s)
Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Hipogonadismo/genética , Mutación , ARN Polimerasa III/genética , Anomalías Dentarias/genética , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Humanos , Datos de Secuencia Molecular
19.
Genes (Basel) ; 15(8)2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39202393

RESUMEN

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals' family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.


Asunto(s)
Histona Demetilasas con Dominio de Jumonji , Mutación Missense , Fenotipo , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Femenino , Masculino , Niño , Preescolar , Adolescente , Adulto , Estudios de Asociación Genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Estudios Retrospectivos , Lactante , Genotipo , Proteínas Nucleares , Proteínas Represoras
20.
Am J Med Genet A ; 161A(12): 3012-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24115501

RESUMEN

Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders.


Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Anomalías del Ojo/genética , Anomalías del Ojo/fisiopatología , Síndrome de Fraser/genética , Macrostomía/genética , Macrostomía/fisiopatología , Anomalías Múltiples/etiología , Proteínas Portadoras/genética , Proteínas de la Matriz Extracelular/genética , Anomalías del Ojo/etiología , Femenino , Síndrome de Fraser/fisiopatología , Humanos , Macrostomía/etiología , Masculino , Mutación , Proteínas del Tejido Nervioso/genética , Fenotipo
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