RESUMEN
22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22-A and LCR22-D. Loss of the TBX1 gene is considered the most important cause of the phenotype. A limited number of patients with smaller, overlapping deletions distal to the TBX1 locus have been described in the literature. In these patients, the CRKL gene is deleted. Haploinsufficiency of this gene has also been implicated in the pathogenesis of 22q11.2 deletion syndrome. To distinguish these deletions (comprising the LCR22-B to LCR22-D region) from the more distal 22q11.2 deletions (located beyond LCR22-D), we propose the term "central 22q11.2 deletions". In the present study we report on 27 new patients with such a deletion. Together with information on previously published cases, we review the clinical findings of 52 patients. The prevalence of congenital heart anomalies and the frequency of de novo deletions in patients with a central deletion are substantially lower than in patients with a common or distal 22q11.2 deletion. Renal and urinary tract malformations, developmental delays, cognitive impairments and behavioral problems seem to be equally frequent as in patients with a common deletion. None of the patients had a cleft palate. Patients with a deletion that also encompassed the MAPK1 gene, located just distal to LCR22-D, have a different and more severe phenotype, characterized by a higher prevalence of congenital heart anomalies, growth restriction and microcephaly. Our results further elucidate genotype-phenotype correlations in 22q11.2 deletion syndrome spectrum.
Asunto(s)
Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Adolescente , Adulto , Niño , Preescolar , Facies , Familia , Femenino , Orden Génico , Sitios Genéticos , Humanos , Masculino , Fenotipo , Diagnóstico Prenatal , Adulto JovenRESUMEN
IMPORTANCE: The NMNAT1 gene was recently found to be mutated in a subset of patients with Leber congenital amaurosis and macular atrophy. The most prevalent NMNAT1 variant was p.Glu257Lys, which was observed in 38 of 106 alleles (35.8%). On the basis of functional assays, it was deemed a severe variant. OBSERVATIONS: The p.Glu257Lys variant was 80-fold less frequent in a homozygous state in patients with Leber congenital amaurosis than predicted based on its heterozygosity frequency in the European American population. Moreover, we identified this variant in a homozygous state in a patient with no ocular abnormalities. CONCLUSIONS AND RELEVANCE: On the basis of these results, the p.Glu257Lys variant is considered not fully penetrant. Homozygotes of the p.Glu257Lys variant in most persons are therefore not associated with ocular disease. Consequently, genetic counselors should exercise great caution in the interpretation of this variant.
Asunto(s)
Amaurosis Congénita de Leber/genética , Mutación , Nicotinamida-Nucleótido Adenililtransferasa/genética , HumanosRESUMEN
OBJECTIVE: Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K(+) /H(+) exchange and in Ca(2+) homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. METHODS: Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1. RESULTS: Three unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1. SIGNIFICANCE: We consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Asunto(s)
Cromosomas Humanos Par 4/genética , Eliminación de Gen , Convulsiones/genética , Síndrome de Wolf-Hirschhorn/genética , Adolescente , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
It is estimated that the human mitochondrial proteome consists of 1000-1500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology. We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. CEP89 is a ubiquitously expressed and highly conserved gene of unknown function. Immunocytochemistry and cellular fractionation experiments showed that CEP89 is present both in the cytosol and in the mitochondrial intermembrane space. Furthermore, we ascertained in vitro that downregulation of CEP89 resulted in a severe decrease in complex IV in-gel activity and altered mobility, suggesting that the complex is aberrantly formed. Two-dimensional BN-SDS gel analysis revealed that CEP89 associates with a high-molecular weight complex. Together, these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. Ubiquitous knockdown of fly Cep89 decreased complex IV activity and resulted in complete lethality. Furthermore, Cep89 is required for mitochondrial integrity, membrane depolarization and synaptic transmission of photoreceptor neurons, and for (sub)synaptic organization of the larval neuromuscular junction. Finally, we tested neuronal Cep89 knockdown flies in the light-off jump reflex habituation assay, which revealed its role in learning. We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Mitocondrias/metabolismo , Neuronas/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Niño , Cromosomas Humanos Par 19 , Deficiencia de Citocromo-c Oxidasa/genética , Deficiencia de Citocromo-c Oxidasa/metabolismo , Citosol , Modelos Animales de Enfermedad , Drosophila/genética , Proteínas de Drosophila/genética , Femenino , Eliminación de Gen , Expresión Génica , Técnicas de Silenciamiento del Gen , Homocigoto , Humanos , Aprendizaje , Proteínas Asociadas a Microtúbulos , Mitocondrias/genética , Mutación , Especificidad de Órganos/genética , Polimorfismo de Nucleótido Simple , Transporte de Proteínas , Sinapsis/genética , Sinapsis/metabolismoRESUMEN
The X-linked Opitz G/BBB syndrome (OS) is a congenital malformation disorder characterized by hypertelorism, swallowing difficulties, hypospadias, and additional midline malformations. Loss of function mutations in the MID1 gene at Xp22.3 are responsible for the X-linked form of OS. Various mutations are found all over the gene but without a clear genotype-phenotype correlation. We describe additional family studies of a previously reported boy with a relatively mild form of OS, caused by the unique p.Lys370Glu (c.1108A>G) mutation in MID1. The same mutation was found in his clinically affected brother but also in the healthy maternal uncle. To our knowledge, this is the first report of a MID1 missense mutation causing non-penetrance in a male.
Asunto(s)
Cromosomas Humanos X , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas de Microtúbulos/genética , Mutación Missense , Proteínas Nucleares/genética , Factores de Transcripción/genética , Esófago/anomalías , Esófago/patología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Hipertelorismo/genética , Hipertelorismo/patología , Hipospadias/genética , Hipospadias/patología , Lactante , Imagen por Resonancia Magnética , Masculino , Ubiquitina-Proteína LigasasRESUMEN
ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation.
Asunto(s)
Cromosomas Humanos X/genética , Eliminación de Gen , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Estudios de Casos y Controles , Mapeo Cromosómico , Estudios de Cohortes , Hibridación Genómica Comparativa , Femenino , Dosificación de Gen , Duplicación de Gen , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Linaje , Fenotipo , Recombinación GenéticaRESUMEN
We report on a female patient with severe mental retardation, dysmorphic features, deafness, spasticity, and behavioural problems in whom a 2.3 Mb duplication of 12q24.21q24.23 was detected by genome-wide tiling-path resolution array-based comparative genomic hybridization. Mental retardation, microcephaly, short stature, recurrent infections, hypotonia and facial features, such as hypertelorism, epicanthal folds, and a broad nasal bridge, were also described in patients with larger duplications overlapping the 12q24.21q24.23 region. The duplicated region contains 16 genes, of which several genes, such as thyroid hormone receptor associated protein 2, replication factor C5 and nitric oxide synthase 1, are expressed in the brain and/or are involved in embryogenesis. The current case shows that microduplications might be a more frequent cause of mental retardation and human malformation than previously appreciated.