Papers by Celia Koiffmann
Nature Genetics, Aug 13, 2006
Recently, the application of array-based comparative genomic hybridization (array CGH) has improv... more 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 5 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.
Journal of Medical Genetics, Jul 1, 1990
A 39 year old male with multiple dysmorphic features was found to have an unstable ring chromosom... more A 39 year old male with multiple dysmorphic features was found to have an unstable ring chromosome 7. Clinical findings are presented and compared with the other five reported cases of ring chromosome 7. The main characteristics found in patients with this chromosome constitution are prenatal onset growth deficiency, bone anomalies, pigmentary or vascular skin changes, and ocular and genital anomalies. Patients with ring chromosome 7 are rare and only five cases have been published using banding tech- niques. Short stature, craniofacial dysmorphism, naevus flammeus, and cafe au lait spots are the main characteristics observed. Two patients had mental retardation and three had intelligence within normal limits. Here we report the sixth case of ring chromo- some 7 in a 39 year old man with mental retardation and multiple malformation syndrome (MCA/MR). The proband was the product of a term pregnancy born to normal, non-consanguineous parents; the mother was 30 years old and the father 32. Birth weight was 2000 g and length was reported to be below normal. He was noted to have microcephaly, a
Two novel pathogenic variants in <i>MED13L</i> : one familial and one isolated case
Journal of Intellectual Disability Research, Oct 28, 2021
BackgroundGenetic variants involving the MED13L gene can lead to an autosomal dominant syndrome c... more BackgroundGenetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism.MethodsWe investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole‐exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome.ResultsTwo MED13L variants have been identified [MED13L(NM_015335.5):c.4417C&gt;T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs.ConclusionsThe two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.
Genetic investigation of syndromic forms of obesity
International Journal of Obesity
Primates, 2020
Howler monkeys (Alouatta), comprising between nine and 14 species and ranging from southern Mexic... more 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.
American journal of medical genetics. Part A, Jan 20, 2017
We describe monozygotic twin girls with genetic variation at two separate loci resulting in a ble... more 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 aty...
An inherited atypical 1 Mb 22qll.2 deletion within the DGS/VCFS 3 Mb region in a child with obesity and aggressive behavior
American Journal of Medical Genetics Part a, 2007
Síndrome de Edwards com aplasia radial-relato de dois casos e revisäo das anomalias esqueléticas na síndrome
Primates, 2010
We have used coalescent analysis of mtDNA cytochrome b (cyt b) sequences to estimate times of div... more We have used coalescent analysis of mtDNA cytochrome b (cyt b) sequences to estimate times of divergence of three species of Alouatta-A. caraya, A. belzebul, and A. guariba-which are in close geographic proximity. A. caraya is inferred to have diverged from the A. guariba/A. belzebul clade approximately 3.83 million years ago (MYA), with the later pair diverging approximately 1.55 MYA. These dates are much more recent than previous dates based on molecular-clock methods. In addition, analyses of new sequences from the Atlantic Coastal Forest species A. guariba indicate the presence of two distinct haplogroups corresponding to northern and southern populations with both haplogroups occurring in sympatry within Sao Paulo state. The time of divergence of these two haplogroups is estimated to be 1.2 MYA and so follows quite closely after the divergence of A. guariba and A. belzebul. These more recent dates point to the importance of Pleistocene environmental events as important factors in the diversification of A. belzebul and A. guariba. We discuss the diversification of the three Alouatta species in the context of recent models of climatic change and with regard to recent molecular phylogeographic analyses of other animal groups distributed in Brazil.
Journal of Human Evolution, 1974
Monkeys Karyotypic studies were carried out on some species belonging to the family Cebidae. The ... more Monkeys Karyotypic studies were carried out on some species belonging to the family Cebidae. The chromosome complunenta have been studied in blood cultures in vitro in the following species: Alouattafkca clamitans (2n = 50); Aotee tGirgutur (2n = 52); Cebw albifrmrc (2n = 52); Cebus sp, (271 = 54); Ateles paniscur @niscus (2n = 34); Lag&ix lagotticha (2n = 62). Comparison between the present results and the karyotypes of the Cebidae described in the literature reveal intraspecitic and interspecific variability in number and structure of the chromosomes. 1. lntrodawtion Karyological data concerning the genus Alouatta have been reported only for the following species : Alouatta seniculus with 44 chromosomes in the diploid complement (Bender & Chu, 1963); Alouatta villosa with 53 chromosomes (Hsu, 1965) and Alouatta caraya with 52 chromosomes (Egozcue & Egozcue, 1966a). The diploid complement of Aotes trivirgatus was described with either 54 or 50 chromosomes (Chiarelli, 1961; Chiarelli & Barberis, 1966), while Brumback et al. (1971) reported karyotypes with 54, 53 and 52 chromosomes in Aotes trivirgatus griseimembra. Constancy in the diploid chromosome number in the genus Ateles has been reported in all species dealt with in the literature. Ateles arachnoides and Ateles paniscus have 34 chromosomes, but no information on their karyotypes is available (Chiarelli, in Chu & Bender, 1962 ; Chiarelli, 196 1). Ateles paniscus chamek has 34 chromosomes with 6 metacentric, 9 submetacentric and 1 acrocentric pairs, while the X chromosome is metacentric and the Y acrocentric (Bender & Mettler, 1958). Ateles belzebuth (Chu & Bender, 1961) and Ateles geofioyi cwullatus (Bender & Mettler, 1958) have identical karyotypes with 34 chromosomes, including 3 metacentric, 9 submetacentric and 1 acrocentric pairs, a metacentric X chromosome and an acrocentric Y. According to Egozcue & Hagemenas (1967), the X chromosome of Ateles geofioyi cucullatus is submetacentric, the Y either acrocentric or submetacentric. The X and Y chromosomes of Ateles geofioyi were described as metacentric by Hsu & Benirschke (1968) and by Egozcue et al. (1969). The karyotype of Lagothrix ubericola was described by Bender & Chu (1963) with 62 chromosomes, and that of Lagothrix lagotricha was recorded from a female specimen with 32 submetacentric and 30 acrocentric chromosomes by Egozcue & Perkins (1970). Cebus capucinus was described with 52 (Egozcue & Egozcue, 19666) and 54 chromosomes (Bender & Mettler, 1958; Egozcue, 1969). The X chromosome was reported to to be either submetacentric or acrocentric and the Y to be acrocentric. Cebus albzj%ons was reported with 54 chromosomes including 3 metacentric, 7 submetacentric and 16 acrocentric pairs in the diploid complement; the X chromosome was submetacentric and the Y acrocentric (Egozcue & Egozcue, 1967). Cebus apella had 54 chromosomes with 3 metacentric, 9 submetacentric and 14 acrocentric pairs in the complement; the X and Y chromosomes were acrocentric (Bender & Mettler, 1958).
Is Shwachman syndrome (McKusick 26040) a chromosome breakage syndrome?
Human Genetics, 1991
... C~lia P. Koiffmann a, Claudette H. Gonzalez 2&amp;quot;3, Deise H. Souza 1, Eliana G. Rom... more ... C~lia P. Koiffmann a, Claudette H. Gonzalez 2&amp;quot;3, Deise H. Souza 1, Eliana G. Romani 1, Chong A. Kim 3, and Anita Wajntal 1 1 ... Johns Hopkins University Press, Balitmore Tada H, Ri T, Yoshida H, Ishimoto K, Kaneko M, Yamashiro Y, Shinohara T (1987) A case of Shwachman ...
The Karyotype of Cacajao melanocephalus (Platyrrhini, Primates)
Folia Primatologica, 1981
Chromosome studies were performed in a male representative of Cacajao melanocephalus. The diploid... more Chromosome studies were performed in a male representative of Cacajao melanocephalus. The diploid number was 45: the chromosome complement consisting of 12 pairs of acrocentric autosomes, 9 pairs of biarmed autosomes and 1 heteromorphic pair composed of one subtelocentric and one acrocentric chromosome. The X chromosome was submetacentric and the Y chromosome was apparently translocated to an acrocentric autosome. G-banding patterns were studied and the results compared to karyotypes previously described for Cacajao rubicundus and Cacajao calvus.
European Journal of Medical Genetics, 2006
Monosomy 1p36 is one of the most commonly observed mental retardation (MR) syndromes that results... more 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
European Journal of Medical Genetics, 2012
We describe a novel chromosome microdeletion at 15q26.1 detected by oligo-array-CGH in a 6-year-o... more We describe a novel chromosome microdeletion at 15q26.1 detected by oligo-array-CGH in a 6-year-old girl presenting with global development delay, epilepsy, autistic behavior and facial dysmorphisms. Although these features are often present in Angelman syndrome, no alterations were present in the methylation pattern of the Prader-WillieAngelman critical region. The deletion encompasses only 2 genes: CHD2, which is part of a gene family already involved in CHARGE syndrome, and RGMA which exerts a negative control on axon growth. Deletion of either or both genes could cause the phenotype of this patient. These results provide a further chromosome region requiring evaluation in patients presenting Angelman features.
Angelman syndrome: Uniparental paternal disomy 15 determines mild epilepsy, but has no influence on EEG patterns
Epilepsy Research, 2005
The authors describe the electroclinical phenotype of four patients with Angelman syndrome (AS) d... more 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.
Clinical Genetics, 1998
We had previously described a patient with an overgrowth syndrome and the chromosome constitution... more We had previously described a patient with an overgrowth syndrome and the chromosome constitution 45,XY,t(15ql5q) (Wajntal et al., DNA Cell Biol 1993: 12: 227-231). Clinical reassessment and the use of molecular studies, including methylation analysis with an SNRPN probe, microsatellite analyses of D15S1 1, GABRB3 and D15S113 loci, and fluorescence in situ hybridization (FISH) using the SNRPN and GABRB3 probes, are consistent with a diagnosis of Angelman syndrome (AS) due to paternal isodisomy. This is the fourth report case of a translocation 15ql5q with paternal uniparental disomy (UPD). Our findings suggest that some patients with clinical featlres of AS have hyperphagia and obesity with overgrowth, and that these features should not rule out a diagnosis of AS. ingelman syndrome (AS) is a neurobehavioral disorder that results from the loss of maternal imprinted gene expression within the chromosome region 15q 1 1-q 13 (1, 2). Patients have severe mental retardation, absence of speech, a happy disposition, outbursts of laughter, ataxia, hyperactivity and seizures (3). To date, four classes of AS patients have been recognized: patients with maternal deletion within 15ql1-q13; cases of paternal uniparental disomy (UPD); patients with an imprinting mutation; and cases with a mutation in the UBE3A gene (2, 4-6). Paternal UPD is a rare event in AS ((7, 8); reviewed in (9)). Several investigators have suggested that paternal UPD cases show a milder phenotype than that seen in AS patients with a typical deletion ((10); reviewed in (9)), although some AS UPD patients do not have milder clinical features (1 1). Of the previously reported cases of AS and UPD, only three have been due to a balanced 15;15 translocation (12-14).
Clinical Genetics, 2004
Prader–Willi syndrome (PWS) can result from a 15q11–q13 paternal deletion, maternal uniparental d... more 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....
Arquivos de Neuro-Psiquiatria, 1991
Crianças com síndrome de Sotos apresentam aceleração do crescimento, macrocrania, padrões acromag... more Crianças com síndrome de Sotos apresentam aceleração do crescimento, macrocrania, padrões acromagalóides e dificuldades iniciais no desenvolvimento neuropsicomotor. A delineação da síndrome e o diagnóstico diferencial estão baseados na avaliação das características clínicas e no histórico evolutivo desses pacientes. Sete pacientes com síndrome de Sotos são descritos, bem como revistas as características clínicas presentes em 198 pacientes da literatura. As dificuldades motoras presentes durante a primeira infância nos pacientes com síndrome de Sotos são responsáveis pelo mau desempenho destas crianças nos testes de QI. A estimulação especializada deve ser encorajada para ajustar os afetados a superarem suas dificuldades iniciais.
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Papers by Celia Koiffmann