Duplication Xp11.22-p14 in females: does X-inactivation help in assessing their significance?

In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic.

Mosaic deletion of EXOC6B: further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability.

We describe a boy with developmental delay, speech delay, and minor dysmorphic features with a heterozygous de novo ∼460 kb deletion at 2p13.2 involving only parts of EXOC6B present in about 50% of lymphocytes. This widely expressed gene encodes the exocyst component 6B, which is part of a multiprotein complex required for targeted exocytosis. Little is known about the effect of EXOC6B haploinsufficiency. In 2008, a patient with a complex syndromic phenotype, including left renal agenesis, neutropenia, recurrent pulmonary infections, long bone diaphysis broadening, growth retardation, and developmental delay (DD) was found to carry a de novo translocation t(2;7) involving TSN3 and EXOC6B. Further characterization of the translocation indicated that disruption of TSN3 may be responsible for the skeletal phenotype. Recently, a heterozygous deletion of EXOC6B along with a deletion of the CYP26B1 gene has been reported in a boy with intellectual disability, speech delay, hyperactivity, facial asymmetry, a dysplastic ear, brachycephaly, and mild joint contractures. Additionally, disruption of EXOC6B by a de novo balanced translocation t(2;8) has been described in a patient with developmental delay, epilepsy, autistic and aggressive behavior. This is the first report of a de novo deletion affecting only EXOC6B in an individual with developmental delay. In conclusion, based on our findings and recent data from the literature, there is evidence that EXOC6B and the exocyst complex might play an important role in the molecular pathogenesis of intellectual disability.

3p25.3 microdeletion of GABA transporters SLC6A1 and SLC6A11 results in intellectual disability, epilepsy and stereotypic behavior.

Small interstitial deletions affecting chromosome region 3p25.3 have been reported in only five patients so far, four of them with overlapping telomeric microdeletions 3p25.3 and variable features of 3p- syndrome, and one patient with a small proximal microdeletion and a distinct phenotype with intellectual disability (ID) and multiple congenital anomalies. Here we report on three novel patients with overlapping proximal microdeletions 3p25.3 of 1.1-1.5 Mb in size showing a consistent non-3p- phenotype with ID, epilepsy/EEG abnormalities, poor speech, ataxia and stereotypic hand movements. The smallest region of overlap contains two genes encoding sodium- and chloride-dependent GABA transporters which have not been associated with this disease phenotype in humans so far. The protein function, the phenotype in transporter deficient animal models and the effects of specific pharmacological transporter inhibition in mice and humans provide evidence that these GABA transporters are plausible candidates for seizures/EEG abnormalities, ataxia and ID in this novel group of patients. A fourth novel patient deleted for a 3.16 Mb region, both telomeric and centromeric to 3p25.3, confirms that the telomeric segment is critical for the 3p- syndrome phenotype. Finally, a region of 643 kb is suggested to harbor one or more genes causative for polydactyly which is part of the 3p- syndrome.

The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome?

Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID). Microduplications of 5q35.2-q35.3 including NSD1 have been reported in only five patients so far and described clinically as a reversed Sos resulting from a hypothetical gene dosage effect of NSD1. Here, we report on nine patients from five families with interstitial duplication 5q35 including NSD1 detected by molecular karyotyping. The clinical features of all 14 individuals are reviewed. Patients with microduplications including NSD1 appear to have a consistent phenotype consisting of short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated. Based on our findings, we discuss the possible etiology and conclude that it is possible, but so far unproven, that a gene dosage effect of NSD1 may be the major cause.

Disruption of SOX6 is associated with a rapid-onset dopa-responsive movement disorder, delayed development, and dysmorphic features.

BACKGROUND: Sox6 is a transcription factor that is crucial for the differentiation and development of cortical interneurons and dopaminergic neurons of the substantia nigra pars compact. Loss-of-function mutations might thus result in complex paroxysmal diseases such as epilepsy syndromes or movement disorders. PATIENT: We present a 15-year-old boy with delayed speech development and attention deficit hyperactivity disorder who presented with a rapid-onset generalized dopa-responsive dystonia. RESULTS: Neurological examination revealed generalized dystonic and frequent athetoid movements of the arms, trunk, and neck. Gait was severely impaired secondary to frequent dystonic postures. Both a resting tremor and action tremors were observed in both hands. Speech was dysarthric but language comprehension was unimpaired. Testing for saccadic dysfunction revealed hypometric horizontal and vertical saccades. Physical examination was otherwise significant for a pectus carinatum and splenomegaly. Laboratory studies, brain magnetic resonance imaging, and electroencephalography were unremarkable. Treatment with levodopa/carbidopa led to a complete and sustained remission of neurological symptoms. Genetic testing revealed a mono-allelic de novo 84-kb deletion on chromosome 11p15.2 encompassing exons 14-16 of the SOX6 gene (chr11: 15944880-16029095, NCBI 37/hg19). CONCLUSIONS: This is the first report of a dopa-responsive movement disorder associated with SOX6 disruption. SOX6 mutations should be considered in the differential diagnosis of unexplained dopa-responsive dystonia syndromes.

Characterization of the first intragenic SATB2 duplication in a girl with intellectual disability, nearly absent speech and suspected hypodontia.

SATB2, a gene encoding a highly conserved DNA-binding protein, is known to have an important role in craniofacial and neuronal development. Only a few patients with SATB2 variants have been described so far. Recently, Döcker et al provided a summary of these patients and delineated the SAS (SATB2-associated syndrome). We here report on a girl with intellectual disability, nearly absent speech and suspected hypodontia who was shown to carry an intragenic SATB2 tandem duplication hypothesized to lead to haploinsufficiency of SATB2. Preliminary information on this patient had already been included in the article by Döcker et al. We want to give a detailed description of the patient's phenotype and genotype, providing further insight into the spectrum of the molecular mechanisms leading to SAS.

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3.

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.

Hipercalcemia secundária à necrose de tecido adiposo subcutâneo / Hypercalcemia secondary to subcutaneous fat necrosis

A necrose de tecido adiposo subcutâneo (NASC) do recém nascido é uma hipodermatite aguda que aparece nas primeiras quatro semanas de vida. Desenvolve-se em crianças vítimas de parto complicado ou de sofrimento fetal. Formam-se placas ou nódulos subcutâneos inflamatórios de coloraçäo violácea e tamanhos variados que costumam regredir espontaneamente dentro de um ano. Pode ser acompanhada de hipercalcemia, por vezes grave, pondo a vida da criança em risco. Descrevemos um caso de NASC em que as lesöes näo eram visíveis e o cálcio plasmático atingiu níveis de 24,5mg/dL. Apesar da hipercalcemia extremamente elevada, o paciente teve evoluçäo satisfatória sendo tratado com hidrataçäo, corticoesteróides e dieta restritiva de cálcio e vitamina D. Alguns aspectos fisiopatológicos e de tratamento säo discutidos