Célia P. Koiffmann

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.

Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations

We report array-CGH screening of 95 syndromic patients with normal G-banded karyotypes and at least one of the following features: mental retardation, heart defects, deafness, obesity, craniofacial dysmorphisms or urogenital tract malformations. Chromosome imbalances not previously detected in normal controls were found in 30 patients (31%) and at least 16 of them (17%) seem to be causally related to the abnormal phenotypes. Eight of the causative imbalances had not been described previously and pointed to new chromosome regions and candidate genes for specific phenotypes, including a connective tissue disease locus on 2p16.3, another for obesity on 7q22.1→q22.3, and a candidate gene for the 3q29 deletion syndrome manifestations. The other causative alterations had already been associated with well-defined phenotypes including Sotos syndrome, and the 1p36 and 22q11.21 microdeletion syndromes. However, the clinical features of these latter patients were either not typical or specific enough to allow diagnosis before detection of chromosome imbalances. For instance, three patients with overlapping deletions in 22q11.21 were ascertained through entirely different clinical features, i.e., heart defect, utero-vaginal aplasia, and mental retardation associated with psychotic disease. Our results demonstrate that ascertainment through whole-genome screening of syndromic patients by array-CGH leads not only to the description of new syndromes, but also to the recognition of a broader spectrum of features for already described syndromes. Furthermore, on the technical side, we have significantly reduced the amount of reagents used and costs involved in the array-CGH protocol, without evident reduction in efficiency, bringing the method more within reach of centers with limited budgets.

Impact of molecular mechanisms, including deletion size, on Prader-Willi syndrome phenotype: study of 75 patients

Prader–Willi syndrome (PWS) can result from a 15q11–q13 paternal deletion, maternal uniparental disomy (UPD), or imprinting mutations. We describe here the phenotypic variability detected in 51 patients with different types of deletions and 24 patients with UPD. Although no statistically significant differences could be demonstrated between the two main types of PWS deletion patients, it was observed that type I (BP1‐BP3) patients acquired speech later than type II (BP2‐BP3) patients. Comparing the clinical pictures of our patients with UPD with those with deletions, we found that UPD children presented with lower birth length and started walking earlier and deletion patients presented with a much higher incidence of seizures than UPD patients. In addition, the mean maternal age in the UPD group was higher than in the deletion group. No statistically significant differences could be demonstrated between the deletion and the UPD group with respect to any of the major features of PWS. In conclusion, our study did not detect significant phenotypic differences among type I and type II PWS deletion patients, but it did demonstrate that seizures were six times more common in patients with a deletion than in those with UPD.

Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects

Angelman syndrome (AS) can result from either a 15q11–q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11–q13 region. There were no major phenotypic differences between the two main classes (BP1–BP3; BP2–BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1–BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2–BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1–BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2–BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del × 22.2% UPD) and hypotonia (73.3% del × 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

A 17q21.31 microdeletion encompassing the MAPT gene in a mentally impaired patient

About 15% of patients with a clinical phenotype of Angelman syndrome (AS) have an unknown etiology. We report a patient with features reminiscent of AS, including a pattern of characteristic facial anomalies as well as speech impairment, developmental delay and frequent laughter. In addition, the patient had features not commonly associated with AS such as heart malformations and scoliosis. She was negative in SNURF-SNRPN exon 1 methylation studies and the G-banded karyotype was normal. Array-based comparative genomic hybridization disclosed a deletion of maximally 1 Mb at 17q21.31. The deleted region contains the MAPT gene, implicated in late onset neurodegenerative disorders, and the STH and NP_056258.1 genes. Another gene, such as CRHR1, might also be included based on maximum possible size of the deletion. We suggest that microdeletions within the 17q21.31 segment should be considered as a possible cause of phenotypes resembling AS, particularly when easily controlled seizures and/or cardiac abnormalities are also present.

Angelman Syndrome: Difficulties in EEG Pattern Recognition and Possible Misinterpretations

Summary:  Purpose: This study aimed to evaluate the sensitivity of the EEG in Angelman syndrome (AS), to verify the age at onset of suggestive EEGs and to study EEG patterns, analyzing variations and comparing our findings with nomenclature previously used.

Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, speech impairment, ataxia, and happy disposition with frequent smiling. AS results from the loss of expression of a maternal imprinted gene, UBE3A, mapped within 15q11‐q13 region, due to different mechanisms: maternal deletion, paternal UPD, imprinting center mutation, and UBE3A mutation. Deletion AS patients may exhibit hypopigmentation of skin, eye, and hair correlating with deletion of P gene localized in the distal part of Prader‐Willi (PWS)/AS region. Our patient presented developmental delay, severe mental retardation, absence of speech, outbursts of laughter, microcephaly, ataxia, hyperactivity, seizures, white skin, no retinal pigmentation, and gold yellow hair. His parents were of African ancestry. The SNURF‐SNRPN methylation analysis confirmed AS diagnosis and microsatellite studies disclosed deletion with breakpoints in BP2 and BP3. All of the 25 exons and flanking introns of the P gene of the patient, his father, and mother were investigated. The patient is hemizygous for the deleted exon 7 of the P gene derived from his father who is a carrier of the deleted allele. Our patient manifests OCA2 associated with AS due to the loss of the maternal chromosome 15 with the normal P allele, and the paternal deletion in the P gene. As various degrees of hipopygmentation are associated with PWS and AS patients, the study of the P gene in a hemizygous state could contribute to the understanding of its effect on human pigmentation during development and to disclose the presence of modifier pigmentation gene(s) in the PWS/AS region.

Paternal UPD15: Further Genetic and Clinical Studies in Four Angelman Syndrome Patients

Among 25 patients diagnosed with Angelman syndrome, we detected 21 with deletion and 4 with paternal uniparental disomy (UPD), 2 isodisomies originating by postzygotic error, and 1 MII nondisjunction event. The diagnosis was obtained by molecular techniques, including methylation pattern analysis of exon 1 of SNRPN and microsatellite analysis of loci within and outside the 15q11-q13 region. Most manifestations present in deletion patients are those previously reported. Comparing the clinical data from our and published UPD patients with those with deletions we observed the following: the age of diagnosis is higher in UPD group (average 7 3/12 years), microcephaly is more frequent among deletion patients, UPD children start walking earlier (average age 2 9/12 years), whereas in deletion patients the average is 4 (1/2) years, epilepsy started later in UPD patients (average 5 10/12 years) than in deletion patients (average 1 11/12 years), weight above the 75th centile is reported mainly in UPD patients, complete absence of speech is more common in the deleted (88.9%) than in the UPD patients because half of the children are able to say few words. Thus, besides the abnormalities already described, the UPD patients have somewhat better verbal development, a weight above the 75th centile, and OFC in the upper normal range.

Rett Syndrome in a Boy with a 47,XXY Karyotype

The collaboration of Drs. Mariz Vainzof, Maria Rita Passos-Bueno, and Lygia V. Pereira and of Constancia Urbani is gratefully acknowledged. This research was supported with grants from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Programa de Apoio a Nucleos de Excelencia, and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico.

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 ∼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.