Genetic investigation of syndromic forms of obesity.

BACKGROUND: Syndromic obesity (SO) refers to obesity with additional phenotypes, including intellectual disability (ID)/developmental delay (DD), dysmorphic features, or organ-specific abnormalities. SO is rare, has high phenotypic variability, and frequently follows a monogenic pattern of inheritance. However, the genetic etiology of most cases of SO has not been elucidated. SUBJECTS AND METHODS: In this study, we investigated 20 SO patients by whole-exome sequencing (WES) trios to identify causal genetic variants. RESULTS: 4/20 patients had negative results for array comparative genomic hybridization (aCGH) analyses. In the remaining 15 patients, in addition to SNVs and indels, CNVs were also evaluated. Pathogenic/likely pathogenic (P/LP) SNVs/indels were detected in 6/20 patients (involving MED13L, AHDC1, EHMT1, MYT1L, GRIA3, and SETD1A), while two patients carried an inherited VUS. In addition, P/LP CNVs were observed in 3/15 patients (involving SATG2, KIAA0442, and MEIS2). CONCLUSIONS: All nine detected P/LP variants involved genes already known to lead to syndromic ID/DD; however, for only two genes (EHMT1 and MYT1L) is the link with obesity well established. This is the first study applying a comprehensive genomic investigation of an SO cohort, showing a high diagnostic yield (~47%). Additionally, our findings suggested that several known ID/DD genes may also predispose individuals to SO.

Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins.

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability.

Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.

Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: report of novel pathogenic copy number variants.

Obesity is a major threat to public health worldwide, and there is now mounting evidence favoring a role for the central nervous system (CNS) in weight control. A causal relationship has been recognized in both monogenic (e.g., BDNF, TRKB, and SIM1 deficiencies) and syndromic forms of obesity [e.g., Prader-Willi syndrome (PWS)]. Syndromic obesity arising from chromosomal abnormalities, that typically also affect learning and development, are often associated with congenital malformations and behavioral characteristics. We report on nine unrelated patients with a diagnosis of learning disability and/or developmental delay (DD) in addition to obesity that were found to have copy number variants (CNVs) by single nucleotide polymorphism array-based analysis. Each patient also had a distinct and complex phenotype, and most had hypotonia and other neuroendocrine issues, such as hyperphagia and hypogonadism. Molecular and clinical characterization of these patients enabled us to determine with confidence that the CNVs we observed were pathogenic or likely to be pathogenic. Overall, the CNVs reported here encompassed a candidate gene or region (e.g., SIM1) that has been reported in patients associating obesity and DD and/or intellectual disability (ID) and novel candidate genes and regions.

Establishment of iPSC lines and zebrafish with loss-of-function AHDC1 variants: Models for Xia-Gibbs syndrome.

Xia-Gibbs syndrome (XGS) is a syndromic form of intellectual disability caused by heterozygous AHDC1 variants, but the pathophysiological mechanisms underlying this syndrome are still unclear. In this manuscript, we describe the development of two different functional models: three induced pluripotent stem cell (iPSC) lines with different loss-of-function (LoF) AHDC1 variants, derived by reprogramming peripheral blood mononuclear cells from XGS patients, and a zebrafish strain with a LoF variant in the ortholog gene (ahdc1) obtained through CRISPR/Cas9-mediated editing. The three iPSC lines showed expression of pluripotency factors (SOX2, SSEA-4, OCT3/4, and NANOG). To verify the capacity of iPSC to differentiate into the three germ layers, we obtained embryoid bodies (EBs), induced their differentiation, and confirmed the mRNA expression of ectodermal, mesodermal, and endodermal markers using the TaqMan hPSC Scorecard. The iPSC lines were also approved for the following quality tests: chromosomal microarray analysis (CMA), mycoplasma testing, and short tandem repeat (STR) DNA profiling. The zebrafish model has an insertion of four base pairs in the ahdc1 gene, is fertile, and breeding between heterozygous and wild-type (WT) animals generated offspring in a genotypic proportion in agreement with Mendelian law. The established iPSC and zebrafish lines were deposited on the hpscreg.eu and zfin.org platforms, respectively. These biological models are the first for XGS and will be used in future studies that investigate the pathophysiology of this syndrome, unraveling its underlying molecular mechanisms.

Burden of Rare Copy Number Variants in Microcephaly: A Brazilian Cohort of 185 Microcephalic Patients and Review of the Literature.

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment.

Molecular phylogenetic inference of the howler monkey radiation (Primates: Alouatta).

Howler monkeys (Alouatta), comprising between nine and 14 species and ranging from southern Mexico to northern Argentina, are the most widely distributed platyrrhines. Previous phylogenetic studies of howlers have used chromosomal and morphological characters and a limited number of molecular markers; however, branching patterns conflict between studies or remain unresolved. We performed a new phylogenetic analysis of Alouatta using both concatenated and coalescent-based species tree approaches based on 14 unlinked non-coding intergenic nuclear regions. Our taxon sampling included five of the seven South American species (Alouatta caraya, Alouatta belzebul, Alouatta guariba, Alouatta seniculus, Alouatta sara) and the two recognized species from Mesoamerica (Alouatta pigra, Alouatta palliata). Similarly to previous studies, our phylogenies supported a Mesoamerican clade and a South American clade. For the South American howlers, both methods recovered the Atlantic Forest endemic A. guariba as sister to all remaining South American species, albeit with moderate support. Moreover, we found no support for the previously proposed sister relationship between A. guariba and A. belzebul. For the first time, a clade composed of A. sara and A. caraya was identified. The relationships among the other South American howlers, however, were not fully supported. Our estimates for divergence times within Alouatta are generally older compared to estimates in earlier studies. However, they conform to recent studies proposing a Miocene age for the Isthmus of Panama and for the uplift of the northern Andes. Our results also point to an early genetic isolation of A. guariba in the Atlantic Forest, in agreement with the hypothesis of biotic exchange across South American rain forests in the Miocene. Collectively, these findings contribute to a better understanding of the diversification processes among howler monkey species; however, they also suggest that further comprehension of the evolutionary history of the Alouatta radiation will rely on broadened taxonomic, geographic, and genomic sampling.

A novel MYT1L mutation in a boy with syndromic obesity: Case report and literature review.

BACKGROUND: Pathogenic variants involving the MYT1L gene lead to an autosomal dominant form of syndromic obesity, characterized by polyphagia, intellectual disability/developmental delay, and behavioral problems, and that a characteristic facial phenotype does not seem to be recognizable. METHODS: Trio whole exome sequencing was performed in a 10-year-old Brazilian male presenting polyphagia, severe early-onset obesity, intellectual disability, speech delay, macrocephaly, frontal bossing, telecanthus, strabismus, and hypogenitalism. Additionally, we performed a literature review of patients carrying non-copy number MYT1L variants. RESULTS: A de novo genetic variant not previously reported in MYT1L (NM_015025.4:c.2990C>A) was identified in the proband and classified as pathogenic. From a literature search, 22 further patients carrying non-copy number MYT1L variants were identified, evidencing that although the associated phenotype is quite variable, intellectual disability/developmental and speech delays are always present. Further, most patients have obesity or overweight due to polyphagia. Macrocephaly, strabismus, behavioral problems, and hand/feet malformations are also recurrent features. CONCLUSIONS: We described the first Brazilian case of MYT1L related syndrome and highlighted clinical characteristics based on the literature. Other syndromic forms of obesity such as Prader-Willi, Bardet-Biedl, Börjeson-Forssman-Lehmann, MORM, Cohen, Alstrom, and Kleefstra type 1 syndromes should be considered in the differential diagnosis. Further, although obesity is frequent, it is not an obligatory feature of all carriers of MYT1L mutations.

Extending the phenotype of monosomy 1p36 syndrome and mapping of a critical region for obesity and hyperphagia.

Rearrangements of 1p36 are the most frequently detected abnormalities in diagnostic testing for chromosomal cryptic imbalances and include variably sized simple terminal deletions, derivative chromosomes, interstitial deletions, and complex rearrangements. These rearrangements result in the specific pattern of malformation and neurodevelopmental disabilities that characterizes monosomy 1p36 syndrome. Thus far, no individual gene within this region has been conclusively determined to be causative of any component of the phenotype. Nor is it known if the rearrangements convey phenotypes via a haploinsufficiency mechanism or through a position effect. We have used multiplex ligation-dependent probe amplification to screen for deletions of 1p36 in a group of 154 hyperphagic and overweight/obese, PWS negative individuals, and in a separate group of 83 patients initially sent to investigate a variety of other conditions. The strategy allowed the identification and delineation of rearrangements in nine subjects with a wide spectrum of clinical presentations. Our work reinforces the association of monosomy 1p36 and obesity and hyperphagia, and further suggests that these features may be associated with non-classical manifestations of this disorder in addition to a submicroscopic deletion of approximately 2-3 Mb in size. Multiplex ligation probe amplification using the monosomy 1p36 syndrome-specific kit coupled to the subtelomeric kit is an effective approach to identify and delineate rearrangements at 1p36.

A rare case of trisomy 15pter-q21.2 due to a de novo marker chromosome.

Supernumerary marker chromosomes (sSMC) may or may not be associated with an abnormal phenotype, depending on the presence of euchromatin, on their chromosomal origin and whether they are inherited. Over 80% of sSMCs are derived from acrocentric chromosomes and half of them include the short arm of chromosome 15. Generally, they appear as bisatellited isodicentric marker chromosomes, most of them are symmetric. These chromosomes are normally originated de novo and are associated with mild to severe intellectual disability but not with physical abnormalities. We report on a patient with an SMC studied using classical and molecular cytogenetic procedures (G and C banding, NOR staining, painting and centromeric fluorescent in situ hybridization (FISH), BAC-FISH, and SKY). The MLPA technique and DNA polymorphic markers were used in order to identify its parental origin. The marker chromosome, monosatellited and monocentric, was found to be derived from a maternal chromosome 15 and was defined as 15pter-q21.2. This is the report of the largest de novo monosatellited 15q marker chromosome ever published presenting detailed cytogenetic and clinical data. It was associated with a phenotype including cardiac defect, absence of septum pellucidum, and dysplasia of the corpus callosum.

Further delineation of nonhomologous-based recombination and evidence for subtelomeric segmental duplications in 1p36 rearrangements.

The mechanisms involved in the formation of subtelomeric rearrangements are now beginning to be elucidated. Breakpoint sequencing analysis of 1p36 rearrangements has made important contributions to this line of inquiry. Despite the unique architecture of segmental duplications inherent to human subtelomeres, no common mechanism has been identified thus far and different nonexclusive recombination-repair mechanisms seem to predominate. In order to gain further insights into the mechanisms of chromosome breakage, repair, and stabilization mediating subtelomeric rearrangements in humans, we investigated the constitutional rearrangements of 1p36. Cloning of the breakpoint junctions in a complex rearrangement and three non-reciprocal translocations revealed similarities at the junctions, such as microhomology of up to three nucleotides, along with no significant sequence identity in close proximity to the breakpoint regions. All the breakpoints appeared to be unique and their occurrence was limited to non-repetitive, unique DNA sequences. Several recombination- or cleavage-associated motifs that may promote non-homologous recombination were observed in close proximity to the junctions. We conclude that NHEJ is likely the mechanism of DNA repair that generates these rearrangements. Additionally, two apparently pure terminal deletions were also investigated, and the refinement of the breakpoint regions identified two distinct genomic intervals ~25-kb apart, each containing a series of 1p36 specific segmental duplications with 90-98% identity. Segmental duplications can serve as substrates for ectopic homologous recombination or stimulate genomic rearrangements.

PRADER-WILLI SYNDROME: WHAT IS THE GENERAL PEDIATRICIAN SUPPOSED TO DO? - A REVIEW. / SÍNDROME DE PRADER WILLI: O QUE O PEDIATRA GERAL DEVE FAZER - UMA REVISÃO.

OBJECTIVE: To carry out a review about Prader-Willi Syndrome based on the most recent data about the subject and to give recommendation for the general pediatricians for early diagnoses and follow-up. DATA SOURCES: Scientific articles in the PubMed and SciELO databases. The research was not limited to a specific time period and included all articles in such databases. DATA SYNTHESIS: The Prader-Willi Syndrome (PWS) is a rare genetic disorder resulting from the loss of imprinted gene expression within the paternal chromosome 15q11-q13. PWS is characterized by endocrine abnormalities, such as growth hormone (GH) deficiency, obesity, central adrenal insufficiency, hypothyroidism, hypogonadism and complex behavioral and intellectual difficulties. PWS individuals also may present other comorbidities, such as sleep disorders, scoliosis, constipation, dental issues and coagulation disorders. The follow-up protocol of the Children's Institute at Universidade de São Paulo is based on four main pillars: diet, exercise, recombinant human growth hormone (rhGH) therapy and behavioral and cognitive issues. The diet must include a caloric restriction of 900 kcal/day, according to the Prader-Willi Eating Pyramid and exercise plan is focused on daily aerobic exercises and postural therapy. The rhGH therapy is highly recommended by the international scientific literature and must be started as soon as the diagnostic is made. The management of behavioral issues is based on strategies to establish routine and rules. CONCLUSIONS: If the general pediatrician becomes more familiar with PWS, the diagnosis and treatment will start earlier, which is essential to improve the quality of life and care for these individuals.

OBJETIVO: Realizar uma revisão sobre a Síndrome de Prader-Willi (SPW) com base nas publicações mais recentes e fornecer recomendações ao pediatra geral para diagnóstico precoce e seguimento. FONTE DE DADOS: Artigos publicados nas bases Pubmed e SciELO. A pesquisa não foi limitada a um período e incluiu todos os artigos das bases de dados. SÍNTESE DOS DADOS: A SPW é uma síndrome genética rara, resultante da perda do imprinting gênico expresso no cromossomo paterno 15q11-q13, sendo caracterizada por alterações endocrinológicas, como deficiência de hormônio de crescimento, obesidade, insuficiência adrenal central, hipotireoidismo, hipogonadismo, além de alterações comportamentais e déficit intelectual. Há outras comorbidades associadas, como distúrbios de sono, escoliose, constipação, problemas dentários e alterações de coagulação. O protocolo de seguimento da SPW do Instituto da Criança da Universidade de São Paulo se baseia em quarto pilares principais: dieta, exercício físico, terapia com hormônio de crescimento humano recombinante (rhGH) e manejo comportamental e cognitivo. A dieta deve ser restrita a 900 kcal/dia, de acordo com a Pirâmide Alimentar do Prader-Willi, e o exercício físico deve ser diário, aeróbico e postural. A terapia com rhGH é fortemente recomendada pela literatura científica internacional e deve ser iniciada assim que for realizado o diagnóstico da síndrome. O manejo do comportamento é realizado com estratégias para estabelecer rotina e regras. CONCLUSÕES: Se a SPW se tornar mais familiar ao pediatra geral, o diagnóstico e o tratamento começarão mais precocemente, o que irá melhorar a qualidade de vida e os cuidados desses pacientes.

Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity.

BACKGROUND: Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype. RESULTS: Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the GNB3 gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility loci. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (CHAMP1), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. PTBP2, TMEM18, MYT1L, POU3F2, SIM1, SH2B1), and also identified other potentially relevant candidates including TAS1R3, ALOX5AP, and GAS6. CONCLUSION: Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.

Epilepsy in patients with angelman syndrome caused by deletion of the chromosome 15q11-13.

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, speech disorder, stereotyped jerky movements, and a peculiar behavioral profile, with a happy disposition and outbursts of laughter. Most patients with AS present with epilepsy and suggestive electroencephalographic patterns, which may be used as diagnostic criteria. OBJECTIVE: To study epilepsy and response to treatment in a series of patients with AS determined by deletion. DESIGN: Parent and caregiver interview and medical record review. SETTING: Epilepsy Center at the University of São Paulo. PATIENTS: Nineteen patients with AS determined by deletion of chromosome 15q11-13. MAIN OUTCOME MEASURES: Epilepsy severity, epilepsy evolution, and response to antiepileptic drug treatment. RESULTS: All patients with AS in this group had generalized epilepsy, and 10 (53%) also had partial epilepsy. Main seizure types were atypical absences and myoclonic and tonic-clonic seizures. Mean age at onset was 1 year 1 month. Epilepsy aggravated by fever occurred in 10 patients (53%) and status epilepticus in 16 (84%). Eighteen patients (95%) had previous or current history of daily seizures, of which 14 (64%) had disabling seizures. Multiple seizure types were observed in 13 patients (53%). History of refractory epilepsy was reported in 16 patients (84%). Parents reported improvement, characterized by decrease in seizure frequency or seizure control, at the mean age of 5.3 years. Therefore, most of these patients had a period of refractory epilepsy; however, improvement occurred during late childhood and puberty. The best therapeutic response was obtained with valproic acid alone or in association with phenobarbital or clonazepam. Epilepsy was aggravated by carbamazepine, oxcarbazepine, and vigabatrin. CONCLUSIONS: Patients with AS with deletion have epilepsy with early onset and stereotyped electroclinical profile regarding seizure type, severity, and response to antiepileptic drug treatment. Another feature of AS is the age-related improvement, even in refractory cases, during late childhood and puberty. These characteristics are not specific to this syndrome but, when inserted in the proper clinical context, may anticipate diagnosis. We believe that AS should be considered a differential diagnosis in developmentally delayed infants with severe, generalized, cryptogenic epilepsy; however, a proper electroclinical delineation of each genetic group is mandatory.

Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems.

Monosomy 1p36 is one of the most commonly observed mental retardation (MR) syndromes that results in a clinically recognizable phenotype including delayed psychomotor development and/or MR, hypotonia, epilepsy, hearing loss, growth delay, microcephaly, deep-set eyes, flat nasal bridge and pointed chin. Besides, a Prader-Willi syndrome (PWS)-like phenotype has been described in patients with 1p36 monosomy. Forty-one patients presenting hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who tested negative for PWS were investigated by FISH and/or microsatellite markers. Twenty-six were analyzed with a 1p-specific subtelomeric probe, and one terminal deletion was identified. Thirty patients (15 of which also studied by FISH) were investigated by microsatellite markers, and no interstitial 1p36 deletion was found. Our patient presenting the 1p36 deletion did not have the striking features of this monosomy, but her clinical and behavioral features were quite similar to those observed in patients with PWS, except for the presence of normal sucking at birth. The extent of the deletion could be limited to the most terminal 2.5 Mb of 1p36, within the chromosomal region 1p36.33-1p36.32, that is smaller than usually seen in monosomy 1p36 patients. Therefore, chromosome 1p36.33 deletion should be investigated in patients with hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who test negative for PWS.

A new case of interstitial 6q16.2 deletion in a patient with Prader-Willi-like phenotype and investigation of SIM1 gene deletion in 87 patients with syndromic obesity.

The association of obesity, phenotypic abnormalities and mental retardation characterizes syndromic obesity. Its most common form is the Prader-Willi syndrome (PWS-- neonatal hypotonia, poor sucking, delayed psychomotor development, hyperphagia, severe obesity, short stature, small hands and feet, hypogonadism, mild to moderate mental retardation and behavioral disorders). A PWS-like phenotype has been described in patients with chromosome abnormalities involving the chromosome region 6q16.2 that includes the SIM1 gene. Herein we report cytogenetic and gene studies including a screening for the SIM1 gene deletion, performed on 87 patients with PWS-like phenotype, and describe the fifth case of syndromic obesity with an interstitial deletion of the chromosome segment 6q16-q21 and suggest that mutational analysis and further studies of the parental origin of chromosome alterations of 6q16.2 in patients with and without PWS-like phenotype are needed to evaluate possible imprinting effects of SIM1 gene and establish the contribution that alterations in this gene makes to the etiology of syndromic and non-syndromic obesity.

Inv dup (15): is the electroclinical phenotype helpful for this challenging clinical diagnosis?

OBJECTIVE: To study the electroclinical phenotype in 5 patients with large supernumerary marker chromosome referred as inv dup (15), in an attempt to analyze the electroclinical spectrum in order to determine if the binomial epilepsy-EEG is stereotyped enough to corroborate this challenging diagnosis. METHODS: Five patients with large inv dup (15) were submitted to EEG and/or V-EEG, with a minimum duration of 2h. Two certified neurophysiologists analyzed all EEG tracings simultaneously, blinded to clinical and molecular data. Epilepsy was characterized by detailed history and a standard questionnaire according to International League Against Epilepsy guidelines and corroborated by V-EEG findings. RESULTS: Epilepsy started during infancy in 4 patients, in 3 with spasms. Spasms were easily controlled in one but not in others. Epilepsy evolved with generalized seizures in two patients and, generalized and focal in one. Currently, 3 patients present refractory epilepsy and two are seizure-free. In one patient, only one isolated episode suggestive of a secondary generalized tonic-clonic event occurred at the age of 12 years without recurrence. Regarding the EEG, patients had distinct features, except for two patients with very high amplitude fast activity, resembling recruiting rhythm. Despite good seizure outcome in 3 patients, EEGs remained remarkably abnormal with frequent epileptiform discharges over poorly organized background. CONCLUSIONS: Our data showed a heterogeneous electroclinical phenotype with generalized and partial epilepsy, presenting distinct degrees of severity and refractoriness. SIGNIFICANCE: Our findings suggest that it is not possible to delineate an electroclinical phenotype in this neurogenetic syndrome. Therefore, inv dup (15) remains as a diagnostic challenge and epilepsy and EEG features are valuable only when inserted in the proper clinical context.

Angelman syndrome: uniparental paternal disomy 15 determines mild epilepsy, but has no influence on EEG patterns.

The authors describe the electroclinical phenotype of four patients with Angelman syndrome (AS) determined by its rarest genetic mechanism-uniparental disomy (UPD). The analysis of ours and published patients showed that in UPD, when epilepsy occurred, it was milder compared to patients with deletion, although a suggestive EEG was observed in most patients. We found that UPD patients do not completely fit the scenario delineated for AS, suggesting that patients determined by different mechanisms should be distinctly addressed, for a better understanding of this syndrome.

Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity.

Obesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified 'new' microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8;12)(p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8;12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137, was detected; t(8;12) has recently been recognized to cause a childhood obesity syndrome due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD.