Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of B139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. European Journal of Human Genetics (2012) 20, 148-154; doi:10.1038/ejhg.2011.167; published online 7 September 2011Keywords: Smith-Magenis syndrome; 17p11.2; RAI1; arrayCGH; mutation; deletion INTRODUCTION Smith-Magenis syndrome (SMS, MIM 182290) is a multiple congenital anomalies and intellectual disability syndrome associated with a deletion of chromosome 17p11. 2. The incidence of SMS is estimated to be B1:15 000-1:25 000 births. 1 SMS is most commonly characterized by a variable degree of intellectual disability including speech and motor delay, craniofacial and skeletal anomalies, sleep disturbance, self-injurious and attention-seeking behaviors. 1,2 Craniofacial features include brachycephaly, midface hypoplasia, tented upper lip, relative prognathism with age and deep-set and hypoteloric eyes. 3,4 Skeletal features include brachydactyly, short stature and short/ broad hands. 3,4 The behavioral phenotype includes onychotillomania, polyembolokoilamania, 'hand licking and page flipping' , 'self-hugging' and hyperactivity. 5 Sleep disturbance is present in 88% of SMS patients and is characterized by difficulty getting to sleep, frequent nocturnal awakenings, early sleep offset and daytime sleepiness with a need for daytime naps. 6,7 SMS clinical features overlap with other intellectual disability syndromes such as Prader-Willi, Williams and Down's syndromes, which often complicate its clinical diagnosis.A majority, B90%, of SMS patients have a deletion of chromosome 17p11.2 that includes the RAI1 gene. 3 The classical SMS deletions span B3.5 Mb of 17p11.2 and are present in B70% of affected individuals.

ABSTRACT. Smith-Magenis syndrome (SMS) is a complex congenital anomaly characterized by craniofacial anomalies, neurological and behavioral disorders. SMS is caused by a deletion in region 17p11.2, which includes the RAI1 gene (90% of cases), or by point mutation in the RAI1 gene (10% of cases). Laboratory diagnosis is through cytogenetic analysis by GTG banding and molecular cytogenetic analysis by FISH. We carried out an active search for patients in Associations of Parents and Friends of Exceptional Children (APAE) of São Paulo and genetic centers in Brazil. Forty-eight patients were screened for mental retardation, craniofacial abnormalities and stereotyped behavior with a diagnosis of SMS. In seven of them, chromosome banding at high resolution demonstrated chromosome 17p11.2 deletions, confirmed by FISH. We also made a meta-analysis of 165 cases reported between 1982 and 2010 to compare with the clinical data of our sample. We demonstrated differences between the frequencies of clinical signs among the cases reported and seven Brazilian cases of this study, such as dental anoma- Brazilian cases of Smith-Magenis syndrome lies, strabismus, ear infections, deep hoarse voice, hearing loss, and cardiac defects. Although the gold standard for diagnosis of SMS is FISH, we found that the GTG banding technique developed to evaluate chromosome 17 can be used for the SMS diagnosis in areas where the FISH technique is not available.

Terminal deletion in the short arm of chromosome 1 results in a disorder described as 1p36 deletion syndrome. The resulting phenotype varies among patients including mental retardation, developmental delay, sensorineural hearing loss, seizures, heart defects, and distinct facies. In the present case, we performed array-comparative genomic hybridization in a boy with multiple congenital malformations presenting some features overlapping the 1p36 deletion phenotype for whom chromosomal analysis did not reveal a terminal deletion in 1p. Results showed complex chromosome rearrangements involving the 1p36.33-p35.3 region. While the mechanism of origin of these rearrangements is still unclear, chromothripsis-a single catastrophic event leading to shattering chromosomes or chromosome regions and rejoining of the segments-has been described to occur in a fraction of cancers. The presence of at least 12 clustered breaks at 1p and apparent lack of mosaicism in the present case suggests that a single event like chromothripsis occurred. This finding suggests that chromothripsis is responsible for some constitutive complex chromosome rearrangements.

The 22q11.2 duplication syndrome has been recently characterized as a new entity with features overlapping the 22q11.2 deletion syndrome. Most 22q11.2 duplications represent reciprocal events of the typical 3-Mb deletions extending between low copy repeat (LCR) 22-A and LCR22-D. It has been suggested that the clinical manifestations observed in patients with 22q11.2 microduplications may range from milder phenotypes to multiple severe defects, and this variability could be responsible for many undetected cases. Here, we report on a patient with a 1.2-Mb microduplication at 22q11.2 spanning LCR22-F and LCR22-H which harbor the SMARCB1 and SNRPD3 genes. The patient presented healed cleft lip, mild facial dysmorphism, cognitive deficit, and delayed language development associated with severe behavioral problems including learning difficulties and aggressive behavior.

We report on a Brazilian patient with a 1.7-Mb interstitial microdeletion in chromosome 1q21.1. The phenotypic characteristics include microcephaly, a peculiar facial gestalt, cleft lip/palate, and multiple skeletal anomalies represented by malformed phalanges, scoliosis, abnormal modeling of vertebral bodies, hip dislocation, abnormal acetabula, feet anomalies, and delayed neuropsychological development. Deletions reported in this region are clinically heterogeneous, ranging from subtle phenotypic manifestations to severe congenital heart defects and/or neurodevelopmental findings. A few genes within the deleted region are associated with congenital anomalies, mainly the RBM8A, DUF1220, and HYDIN2 paralogs. Our patient presents with a spectrum of unusual malformations of 1q21.1 deletion syndrome not reported up to date.

The chromosome interval 10p15.3p14 harbors about a dozen genes. This region has been implicated in a few well-known human phenotypes, namely HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) and DGS2 (DiGeorge syndrome 2), but a number of variable phenotypes have also been reported. Cleft lip/palate seems to be a very unusual finding within the clinical spectrum of patients with this deletion. Here, we report a male child born with short stature, cleft lip/palate, and feeding problems who was found to have a 5.6-Mb deletion at 10p15.3p14.

TP53 gene mutation is the most common genetic alteration in human malignant tumors and is mainly responsible for Li-Fraumeni syndrome. Among the several cancers related to this syndrome, breast cancer (BC) is the most common. The TP53 p.R337H germline pathogenic variant is highly prevalent in Brazil’s South and Southeast regions, accounting for 0.3% of the general population. We investigated the prevalence of TP53 germline pathogenic variants in a cohort of 83 BC patients from the Midwest Brazilian region. All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like (LFL) syndromes criteria. The samples were tested using next generation sequencing for TP53. Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One (1.2%) patient showed a large TP53 deletion (exons 2–11), which was also confirmed. The p.R337H variant was detected in only one patient. In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.

A síndrome de Williams-Beuren (WBS) resulta de uma deleção hemizigótica de aproximadamente 1,5 Mb a 1,8 Mb na região do cromossomo 7 (7q11.23) e leva a um raro perfil genético multissistêmico. Faces típicas, cardiopatias congênitas, distúrbios do tecido conjuntivo aliados aos déficits de aprendizado e crescimento, personalidade diferenciada e perfil cognitivo que compõem o conjunto de sinais clínicos, que caracterizam a SWB. A etiologia genética compreende uma região de 28 genes de cópia única, ligados a duas regiões repetitivas (LCR - Low Copy Repeats). O teste citogenético molecular (hibridização fluorescente in situ  - FISH) é usado como o padrão ouro para confirmar a exclusão de uma cópia do gene da elastina. O presente estudo teve como objetivo avaliar a prevalência de sinais clínicos de 207 indivíduos com SWB de cinco Estados do Brasil, os quais foram confirmados pela metodologia do teste de FISH, a fim de estabelecer a frequência das características clínicas do SWB e observar possíveis divergências clínicas entre esses. Também se comparam as frequências das características clínicas mais comuns observadas neste grupo com as características clínicas de pacientes brasileiros com SWB relatadas na literatura. Embora se tenham observado algumas diferenças nas frequências das características clínicas do SWB nos diferentes Estados brasileiros, nenhuma delas foi altamente significativa. Portanto, não há evidências de que existam diferenças morfológicas ou funcionais regionais, que possam se refletir no fenótipo de SWB entre os pacientes brasileiros.   Palavras-chave: Síndrome de Williams-Beuren. Cromossomo 7. FISH. Microdeleção.   Abstract Williams-Beuren syndrome (WBS) results from a hemizygous deletion of approximately 1.5Mb to 1.8Mb in the region of chromosome 7 (7q11.23) and leads to a rare multisystem genetic profile. Typical faces, congenital heart disease, connective tissue disorders combined with learning and growth deficits, differentiated personality and cognitive profile make the set of clinical signs that characterize WBS. Genetic etiology comprises a region of 28 single copy genes, linked to two repetitive regions (LCR – Low Copy Repeats). Molecular cytogenetic testing (fluorescent in situ hybridization or FISH) is used as the gold standard to confirm deletion of an  elastin gene copy. The present study aimed to assess the prevalence of clinical signs of 207  WBS  individuals  from five states of Brazil, which were confirmed by the FISH test,  in order to establish the frequency of clinical characteristics of SWB and observe possible clinical divergences between them.It was also compared the frequencies of the most common clinical characteristics observed in the  group in this study with the clinical characteristics of Brazilian patients with SWB reported in the literature.Although some differences were observed in the frequencies of clinical features of SWB in different Brazilian states, none of them was highly significant. Therefore, there is no evidence that there are regional morphological or functional differences that can be reflected in the SWB phenotype among Brazilian patients.   Keywords: Williams-Beuren Syndrome. C­­hromosome 7. FISH; Microdelection.