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1.
Am J Hum Genet ; 110(12): 2015-2028, 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-37979581

RESUMEN

We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32-0.38, p < 10-126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10-4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24-0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09-0.22, p < 10-92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05-0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.


Asunto(s)
Trastorno Autístico , Trastorno Bipolar , Niño , Humanos , Virulencia , Padres , Familia , Trastorno Autístico/genética , Trastorno Bipolar/genética
2.
Cytogenet Genome Res ; 162(7): 365-371, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36758534

RESUMEN

Neurodevelopmental syndromes due to copy number variation are well-known clinical entities. While the numerical variation of gene-harboring regions has been widely investigated at both molecular and clinical levels, much less is understood about unbalanced expression of long noncoding RNAs. Few studies have been performed on the clinical consequences of such unbalanced expression. Heterozygous deletions of NRXN1 have been well described to cause neuropsychological features. Heterozygous deletion of adjacent long noncoding RNA AK127244, either isolated or combined with partial NRXN1 deletion, was recently reported in association with neurodevelopmental delay. In our retrospective study, we analyze a bicentric cohort of 4 individuals, comprising 2 siblings, which bear an isolated heterozygous deletion in long noncoding RNA AK127244 and present with nonsyndromic neurodevelopmental delay.


Asunto(s)
Trastornos del Neurodesarrollo , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión de Célula Nerviosa/genética , Estudios Retrospectivos , Variaciones en el Número de Copia de ADN , Trastornos del Neurodesarrollo/genética
3.
Hum Genet ; 138(2): 187-198, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30656450

RESUMEN

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.


Asunto(s)
Actinas/genética , Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Enfermedades Genéticas Congénitas/diagnóstico por imagen , Microcefalia/genética , Trastornos del Neurodesarrollo/genética , Cuadriplejía/genética , Espasmos Infantiles/genética , Niño , Preescolar , Cromatina/genética , Metilación de ADN/genética , Femenino , Enfermedades Genéticas Congénitas/genética , Humanos , Lactante , Recién Nacido , Masculino , Microcefalia/diagnóstico por imagen , Trastornos del Neurodesarrollo/diagnóstico por imagen , Linaje , Cuadriplejía/diagnóstico por imagen , Espasmos Infantiles/diagnóstico por imagen
4.
Genet Med ; 21(4): 816-825, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30190612

RESUMEN

PURPOSE: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. METHODS: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. RESULTS: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. CONCLUSION: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.


Asunto(s)
Trastorno Autístico/genética , Moléculas de Adhesión Celular Neuronal/genética , Tamización de Portadores Genéticos , Metiltransferasas/genética , Proteínas del Tejido Nervioso/genética , Proteínas/genética , Trastorno Autístico/fisiopatología , Proteínas de Unión al Calcio , Cromosomas Humanos Par 16/genética , Cognición/fisiología , Proteínas del Citoesqueleto , Variaciones en el Número de Copia de ADN/genética , Femenino , Regulación de la Expresión Génica/genética , Antecedentes Genéticos , Humanos , Masculino , Moléculas de Adhesión de Célula Nerviosa , Padres , Linaje , Fenotipo , Eliminación de Secuencia/genética , Hermanos , Factores de Transcripción
6.
Am J Med Genet A ; 164A(8): 1923-30, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24733578

RESUMEN

Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.


Asunto(s)
Antígenos Nucleares/genética , Duplicación Cromosómica , Trisomía/diagnóstico , Trisomía/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Adolescente , Adulto , Anciano , Encéfalo/patología , Proteínas de Ciclo Celular , Niño , Preescolar , Puntos de Rotura del Cromosoma , Mapeo Cromosómico , Cromosomas Humanos X/genética , Hibridación Genómica Comparativa , Exones , Facies , Femenino , Estudios de Asociación Genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Aberraciones Cromosómicas Sexuales , Síndrome , Adulto Joven
7.
J Med Genet ; 50(12): 802-11, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24123876

RESUMEN

BACKGROUND: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. OBJECTIVES: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. METHODS AND RESULTS: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. CONCLUSIONS: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.


Asunto(s)
Exoma/genética , Discapacidad Intelectual/genética , Mutación/genética , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Masculino , Linaje
8.
PLoS Genet ; 7(7): e1002173, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21779178

RESUMEN

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.


Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Padres , Cromosomas en Anillo , Eliminación de Secuencia/genética , Translocación Genética , Adulto Joven
9.
medRxiv ; 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39252907

RESUMEN

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion and CHD8 variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.

10.
Genes Genomics ; 45(4): 491-505, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36807877

RESUMEN

BACKGROUND: Individuals with the 2p15p16.1 microdeletion syndrome share a complex phenotype including neurodevelopmental delay, brain malformations, microcephaly, and autistic behavior. The analysis of the shortest region of overlap (SRO) between deletions in ~ 40 patients has led to the identification of two critical regions and four strongly candidate genes (BCL11A, REL, USP34 and XPO1). However, the delineation of their role in the occurrence of specific traits is hampered by their incomplete penetrance. OBJECTIVE: To better delineate the role of hemizygosity of specific regions in selected traits by leveraging information both from penetrant and non - penetrant deletions. METHODS: Deletions in patients that do not present a specific trait cannot contribute to delineate the SROs. We recently developed a probabilistic model that, by considering also the non - penetrant deletions, allows a more reliable assignment of peculiar traits to specific genomic segments. We apply this method adding two new patients to the published cases. RESULTS: Our results delineate an intricate pattern of genotype - phenotype correlation where BCL11A emerges as the main gene for autistic behavior while USP34 and/or XPO1 haploinsufficiency are mainly associated with microcephaly, hearing loss and IUGR. BCL11A, USP34 and XPO1 genes are broadly related with brain malformations albeit with distinct patterns of brain damage. CONCLUSIONS: The observed penetrance of deletions encompassing different SROs and that predicted when considering each single SRO as acting independently, may reflect a more complex model than the additive one. Our approach may improve the genotype/phenotype correlation and may help to identify specific pathogenic mechanisms in contiguous gene syndromes.


Asunto(s)
Microcefalia , Humanos , Microcefalia/genética , Deleción Cromosómica , Fenotipo , Estudios de Asociación Genética , Factores de Transcripción/genética
11.
medRxiv ; 2023 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-37292616

RESUMEN

We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross-disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of "genetic anticipation" associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.

12.
Genes (Basel) ; 13(12)2022 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-36553517

RESUMEN

The NFIA (nuclear factor I/A) gene encodes for a transcription factor belonging to the nuclear factor I family and has key roles in various embryonic differentiation pathways. In humans, NFIA is the major contributor to the phenotypic traits of "Chromosome 1p32p31 deletion syndrome". We report on two new cases with deletions involving NFIA without any other pathogenic protein-coding gene alterations. A cohort of 24 patients with NFIA haploinsufficiency as the sole anomaly was selected by reviewing the literature and public databases in order to analyze all clinical features reported and their relative frequencies. This process was useful because it provided an overall picture of the phenotypic outcome of NFIA haploinsufficiency and helped to define a cluster of phenotypic traits that can facilitate clinicians in identifying affected patients. NFIA haploinsufficiency can be suspected by a careful observation of the dysmorphisms (macrocephaly, craniofacial, and first-finger anomalies), and this potential diagnosis is strengthened by the presence of intellectual and developmental disabilities or other neurodevelopmental disorders. Further clues of NFIA haploinsufficiency can be provided by instrumental tests such as MRI and kidney urinary tract ultrasound and confirmed by genetic testing.


Asunto(s)
Megalencefalia , Sistema Urinario , Humanos , Factores de Transcripción NFI/genética , Haploinsuficiencia/genética , Megalencefalia/genética , Deleción Cromosómica
13.
Genes (Basel) ; 13(11)2022 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-36360163

RESUMEN

The authors report on a boy with dyslexia and attention deficit hyperactivity disorder. A protocol of standardized tests assessed the neuroadaptive profile, allowing deep neuropsychiatric phenotyping. In addition to the diagnosis of dyslexia and attention deficit hyperactivity disorder, such methodology led to endeavor cognitive, adaptive, and academic skills. Chromosomal microarray analysis detected a 452.4 Kb de novo heterozygous microdeletion in chromosomal region 1p34.3, including seven OMIM genes. The authors took a thorough evaluation of the association to the phenotype of the deleted genes. Further reports could strengthen such association.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Dislexia , Humanos , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/genética , Dislexia/diagnóstico , Dislexia/genética , Heterocigoto , Fenotipo
14.
Genes (Basel) ; 12(5)2021 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-33925474

RESUMEN

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.


Asunto(s)
Cromosomas Humanos Par 8/genética , Eliminación de Secuencia/genética , Adolescente , Adulto , Trastorno del Espectro Autista/genética , Niño , Preescolar , Deleción Cromosómica , Disfunción Cognitiva/genética , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Microcefalia/genética , Fenotipo
15.
Eur J Hum Genet ; 27(4): 594-602, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30659260

RESUMEN

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.


Asunto(s)
Atrofia/genética , Ataxia Cerebelosa/genética , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Atrofia/fisiopatología , Ataxia Cerebelosa/fisiopatología , Consanguinidad , Variaciones en el Número de Copia de ADN/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Hermanos
16.
Brain Dev ; 30(6): 425-9, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18166284

RESUMEN

Studies of epilepsy associated with chromosomal abnormalities may provide information about clinical and EEG phenotypes and possibly to identify new epilepsy genes. We describe a female patient with intractable focal epilepsy, borderline intellectual functioning, and facial dysmorphisms, in whom genetic study (i.e., karyotype and array-CGH analysis) revealed a distal trisomy 4p and distal monosomy Xq. Although any genetic hypothesis remains speculative, several genes are located in the 4p chromosome segment involved in the rearrangement, some of which may be related to epilepsy.


Asunto(s)
Cromosomas Humanos Par 4 , Cromosomas Humanos X , Epilepsias Parciales/genética , Monosomía , Trisomía/genética , Adulto , Aberraciones Cromosómicas , Electroencefalografía , Epilepsias Parciales/fisiopatología , Humanos , Cariotipificación , Masculino
17.
Hum Mutat ; 21(5): 529-34, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12673795

RESUMEN

Molecular defects affecting the ATRX gene lead to the ATRX syndrome (alpha thalassemia/mental retardation syndrome, X-linked), characterized by severe mental retardation, microcephaly, distinct facial dysmorphism, and genital abnormalities, as well as a wide spectrum of other pathological features. Alpha thalassemia is frequent but does not represent a constant characteristic of the syndrome. An expanding phenotype of the ATRX gene (a RAD54 homologue encoding a putative zinc-finger helicase) has been demonstrated as a result of the association of single mutations with specific X-linked mental retardation syndromes. To date, mutational analysis of the gene has been based on direct DNA sequencing or using methods with a lower detection rate. In this paper, we present a broad-range DGGE method for single-step mutation scanning of the entire open reading frame (ORF) and canonical splice sites of the gene. Using this method, we successfully identified five novel sequence changes in the ATRX gene, including four missense mutations (K1733E, R2085C, D2136N, T2169A) and one polymorphism (IVS5+35G>A).


Asunto(s)
ADN Helicasas/genética , Análisis Mutacional de ADN/métodos , Electroforesis en Gel de Poliacrilamida/métodos , Proteínas Nucleares/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Cromosomas Humanos X/genética , ADN/química , ADN/genética , Ligamiento Genético , Humanos , Discapacidad Intelectual/complicaciones , Mutación , Sensibilidad y Especificidad , Síndrome , Proteína Nuclear Ligada al Cromosoma X , Talasemia alfa/complicaciones
18.
J Autism Dev Disord ; 42(10): 2202-7, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22222775

RESUMEN

Brachidactyly-Mental Retardation (BDMR) Syndrome (MIM 600430) is associated with terminal deletions at chromosome 2q37 and a limited number of studies also reported an association between 2q37 â†’ qter deletion and autism. Herein we describe two cases of autism in unrelated children with BDMR Syndrome, showing physical, cognitive, behavioral, and disease natural history homologies, with a very prominent social impairment in the first 4 years of life. At follow-up evaluations, spanning a 5-years period, both children experienced a progressive reduction of the autistic symptoms, besides retaining compromised cognitive ability. This report supports the hypothesis that genes in the 2q37 region may contribute to the etiology of autism, leading, however, to a peculiar evolution of the disease, with symptoms severity decreasing over time.


Asunto(s)
Trastorno Autístico/complicaciones , Braquidactilia/complicaciones , Trastornos de los Cromosomas/complicaciones , Displasia Fibrosa Poliostótica/complicaciones , Discapacidad Intelectual/complicaciones , Trastorno Autístico/psicología , Braquidactilia/psicología , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/psicología , Cromosomas Humanos Par 2 , Femenino , Displasia Fibrosa Poliostótica/psicología , Humanos , Discapacidad Intelectual/psicología , Masculino
19.
Dev Med Child Neurol ; 50(6): 473-6, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18384621

RESUMEN

Periventricular nodular heterotopia and Miller-Dieker syndrome are two different disorders of brain development. Miller-Dieker syndrome exhibits classical lissencephaly and is related to defects in the lissencephaly gene (LIS1). Periventricular nodular heterotopia is characterized by aggregates of grey matter adjacent to the lateral ventricle and is mainly linked to mutations in the Filamin A (FLNA) gene. We describe a male infant presenting with facial dysmorphisms resembling those of Miller-Dieker syndrome, neuromotor delay, and drug - resistant infantile spasms. Magnetic resonance imaging of the brain showed periventricular nodular heterotopia overlaid by classical lissencephaly with complete agyria. Cytogenetic and molecular investigations detected a maternally inherited unbalanced translocation involving chromosome arms 17p and 12q. This resulted in partial monosomy of 17p13.3-->pter and partial trisomy of 12q24.3-->qter. No mutation was found in the FLNA gene. The patient died at the age of 22 months from respiratory insufficiency during an infection of the lower respiratory tract. Our observation extends the list of the overlying cortical malformations associated with periventricular nodular heterotopia. It remains to be established whether this peculiar neuronal migration disorder represents a phenotype totally linked to 17q13.3 deletion or results from a combination of gene defects at 17q13.3 and 12q24.3.


Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 13/genética , Lisencefalia/genética , Heterotopia Nodular Periventricular/genética , Translocación Genética/genética , Ventrículos Cerebrales/patología , Citogenética , Lateralidad Funcional/fisiología , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Heterotopia Nodular Periventricular/patología
20.
Am J Med Genet B Neuropsychiatr Genet ; 141B(6): 584-90, 2006 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-16823807

RESUMEN

Within the framework of a FISH screening protocol to detect cryptic subtelomeric rearrangements in autistic disorder (AD), a patient bearing three copies of the subtelomeric portion of the q arm of chromosome 13 has been identified. Beside AD, the patient also has severe mental retardation and displays several dysmorphic features. Further FISH analyses revealed that the trisomy was caused by the translocation of a 13q subtelomeric fragment to the acrocentric tip of one chromosome 21 [46,XY.ish der(21) t(13;21) (q34;p13)(D13S1825+)]. Gene dosage experiments carried out with three multiallelic polymorphisms of the subtelomeric region of chromosome 13q showed that the putative length of the triplicate region does not exceed 300 kb about, that is, the distance from telomere to the first normally inherited marker. In addition, gene dosage analysis performed on the derivative chromosome 21, did not reveal loss of the most telomeric protein-encoding genes on 21p. The potential relationship between a postulated increased expression of genes on 13q34 and the complex phenotype in this trisomic patient is discussed.


Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 13 , Telómero , Translocación Genética , Trisomía , Adolescente , Adulto , Niño , Femenino , Dosificación de Gen , Humanos , Hibridación Fluorescente in Situ , Masculino , Reacción en Cadena de la Polimerasa
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