To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history.
Data from 21 401 families were gathered between ...1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient.
The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%).
Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.
NGS‐based multiple gene panel resequencing in combination with a high resolution CGH‐array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk ...patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and 10 other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients.
What's new?
Risk for hereditary breast and ovarian cancer (HBOC) is mainly determined by BRCA1/2 mutations but in ~60% of cases the genetic predisposition remains unknown. The authors screened more than 200 women with BRCA1/2‐negative HBOC for new pathogenic variants using a combination of multi‐gene panel sequencing and comparative genomic hybridization. A remarkably high frequency of truncating variants in FANCM were discovered, a protein recently suggested as a susceptibility gene for hereditary breast cancer. The authors recommend that combined methods be used to identify new variants for HBOC risk assessment.
RESUMO O objetivo deste trabalho foi comparar a fisioterapia com brinquedos com a terapia assistida por cães no desenvolvimento neuromotor de lactentes de quatro meses de idade com e sem alterações ...neuromotoras. Trata-se de pesquisa descritiva e observacional de caráter qualitativo, realizada com 10 lactentes, que foram avaliados pela escala motora infantil de Alberta (EMIA), divididos em grupo 1 (G1) e grupo 2 (G1) e subdivididos em grupo brinquedo (G1B e G2B) e grupo cão (G1C e G2C) para a realização das intervenções quinzenais. O questionário Affordances in the Home Environment for Motor Development - Infant Scale (AHEMD-IS) foi escolhido para avaliar as oportunidades presentes no ambiente domiciliar. A análise de dados qualitativos foi feita por meio de fotos e filmagens. A presença do cão nos grupos G1C e G2C resultou em um ambiente descontraído e divertido, interesse dos lactentes em tocar o pelo do animal, movimentos alternados de membros, contato visual, emissão de sons, evolução na interação social e sentimento de segurança. Nos grupos G1B e G2B, constatou-se diminuição da motivação, ausência de emissão de sons pelos lactentes e contato visual e interesse pelo toque restrito a brinquedos que tivessem diversas cores e sons, havendo pouca agitação e motivação para as habilidades motoras nesses grupos. Conclui-se que a presença do cão promoveu melhores resultados motores, sociais, afetivos e cognitivos. A terapia assistida por animais pode ser um método eficaz para auxiliar na fisioterapia convencional de lactentes com atraso no desenvolvimento neuropsicomotor.
ABSTRACT This study aimed to compare physical therapy with toys with dog-assisted therapy in the neuromotor development of 4-month-old infants with and without neuromotor alterations. This is a qualitative descriptive and observational study carried out with 10 infants, who were evaluated by the Alberta Infant Motor Scale, divided into Group 1 (G1) and Group 2 (G1), and subdivided into Toy Group (TG1 and TG2) and Dog Group (DG1 and DG2) for the performance of fortnightly interventions. By the Affordances in the Home Environment for Motor Development - Infant Scale, we assessed the opportunities present in the home environment. Qualitative data were analyzed using photos and videos. The presence of a dog in DG1 and DG2 resulted in a relaxed and fun environment, infants interested in touching the animal’s fur, alternating limb movements, eye contact, sound production, increased social interaction, and feeling of security. In TG1 and TG2, decrease in motivation was observed as well as the absence of sound production and eye contact by infants, and interest in touch restricted to toys that had different colors and sounds, with little agitation and motivation for motor skills in those groups. We concluded that the dog’s presence promoted better motor, social, affective, and cognitive results. Animal-assisted therapy can be an effective method to support conventional physical therapy for infants with delayed neuropsychomotor development.
RESUMEN El objetivo de este estudio fue comparar la fisioterapia con juguetes con la terapia asistida por perros en el desarrollo neuromotor de los lactantes de cuatro meses con y sin trastornos neuromotores. Se trata de una investigación cualitativa, descriptiva y observacional, realizada con 10 lactantes, quienes fueron evaluados por la escala motora infantil de Alberta (EMIA), divididos en grupo 1 (G1) y grupo 2 (G1), y subdivididos en grupo juguete (G1J y G2J) y el grupo con perro (G1P y G2P) para realizar las intervenciones quincenales. El cuestionario Affordances in the Home Environment for Motor Development - Infant Scale (AHEMD-IS) se aplicó para evaluar las oportunidades presentes en el entorno domiciliario. El análisis de los datos cualitativos se realizó a partir de fotografías y filmaciones. La presencia del perro en los grupos G1P y G2P resultó en un ambiente relajado y divertido, interés de los lactantes por tocar el pelaje del animal, alternancia de movimientos de las extremidades, contacto visual, emisión de sonidos, evolución en la interacción social y sensación de seguridad. En los grupos G1J y G2J hubo disminución de la motivación, ausencia de emisión de sonidos por parte de los lactantes y contacto visual e interés por el tacto restringido a los juguetes que tenían diferentes colores y sonidos, además de haber poca agitación y motivación para la motricidad en estos grupos. Se concluyó que la presencia del perro promovió mejores resultados motrices, sociales, afectivos y cognitivos. La terapia asistida por animales puede ser un método eficaz para ayudar en la fisioterapia convencional para los lactantes con retraso en el desarrollo neuropsicomotor.
Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early ...death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.
Purpose
The purpose of this study is to characterize a novel structural variant, a large duplication involving exons 1–19 of the
BRCA1
gene in four independent families, and to provide diagnostically ...valuable information including the position of the breakpoints as well as clues to its clinical significance.
Methods
The duplication of exons 1–19 of the
BRCA1
gene was initially detected by routine laboratory testing including MLPA analysis and next generation sequencing. For detailed characterization we performed array-comparative genome hybridization analysis, fluorescent
in situ
hybridization, next generation mapping, and long-distance PCR for break-point sequencing.
Results
Our data revealed a tandem duplication on chromosome 17 that encompassed 357 kb and included exons 1–19 of the
BRCA1
gene and the genes
NBR2
,
NBR1
,
TMEM106A
,
LOC100130581
,
ARL4D
,
MIR2117
up to parts of the
DHX8
gene. This structural variant appeared as a tandem duplication with breakpoints in intron 19 of the
BRCA1
gene and in intron 3 of the
DHX8
gene (HGVS:chr17(hg19):g.41210776_41568516dup). Segregation analysis indicated that this structural rearrangement is phased
in trans
with a known pathogenic exon deletion of the
BRCA1
gene in one family.
Conclusions
The copy number variation initially recognized as duplication of exon 1–19 of the
BRCA1
gene by MLPA analysis is a structural variation with breakpoints in the
BRCA1
and
DHX8
genes. Although currently to be classified as a variant of unknown significance, our family data indicates that this duplication may be a benign variation or at least of markedly reduced penetrance since it occurs
in trans
with another known fully pathogenic variant in the
BRCA1
gene.
We report here on the first family with short stature and Silver-Russell-like phenotype due to a microdeletion in 12q14.3. The Netchine-Harbison clinical scoring system was used for the clinical ...diagnosis of Silver-Russell syndrome (SRS). The three affected first-degree relatives (index patient, mother and brother) presented with prenatal and postnatal growth retardation, feeding difficulties, a prominent forehead and a failure to thrive, but did not show relative macrocephaly. In addition, our index patient showed dysmorphic facial features, periodically increased sweating, and scoliosis. Learning problems and cardiac arrhythmia presented as additional features of her brother. Using high-resolution array-CGH, heterozygosity for a 1.67 Mb deletion in 12q14.3 was detected in the index patient. The heterozygous loss was confirmed by MLPA in the index patient and the other two affected family members. The deletion includes the genes HMGA2, LLPH, TMBIM4, IRAK3, HELB, GRIP1, and the pseudogene RPSAP52. We conclude from these results and from the data of other patients reported in the literature that haploinsufficiency of HMGA2 leads to the short stature in this family.
Abstract We report on an 8-year-old boy with autism spectrum disorder (ASD), speech delay, behavioural problems, disturbed sleep and macrosomia including macrocephaly carrying a microdeletion that ...contains the entire NCAM2 gene and no other functional genes. Other family members with the microdeletion show a large skull circumference but do not exhibit any symptoms of autism spectrum disorder. Among many ASD-candidate genes, NCAM2 has been assumed to play a pivotal role in the development of ASD because of its function in the outgrowth and bundling of neurites. Our reported case raises the questions whether the NCAM2 -deletion is the true cause of the ASD or only a risk factor and whether there might be any connection in NCAM2 with skull-size Key words: autism spectrum disorder, macrocephaly, neural cell adhesion molecule 2 protein (NCAM2), array comparative genomic hybridization (microarray).
When a known microimbalance affecting multiple genes is detected in a patient with syndromic intellectual disability, it is usually presumed causative for all observed features. Whole exome ...sequencing (WES) allows questioning this assumption. In this study of three families with children affected by unexplained syndromic intellectual disability, genome-wide copy number and subsequent analyses revealed a de novo maternal 1.1 Mb microdeletion in the 14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two inherited 22q11.21 microduplications of 2.5 or 2.8 Mb. In patient 1 carrying the 14q32 microdeletion, tall stature and renal malformation were unexplained by paternal UPD(14), and there was no altered
DLK1
expression or unexpected methylation status. By WES and filtering with a mining tool, a novel
FBN1
missense variant was found in patient 1 and his mother, who both showed clinical features of Marfan syndrome by thorough anthropometric assessment, and a novel
EYA1
missense variant as a probable cause of the renal malformation in the patient. In patient 2 with the 22q11.21 microduplication syndrome, skin hypo- and hyperpigmentation and two malignancies were only partially explained. By WES, compound heterozygous
BLM
stop founder mutations were detected causing Bloom syndrome. In male patient 3 carrying a 22q11.21 microduplication inherited from his unaffected father, WES identified a novel missense variant in the
OPHN1
X-linked intellectual disability gene inherited from the unaffected mother as a possible additional cause for developmental delay. Thus, WES seems warranted in patients carrying microdeletions or microduplications, who have unexplained clinical features or microimbalances inherited from an unaffected parent.
Sudden infant death syndrome (SIDS) is currently the major cause of an unexpected and unexplained death of infants in the first year of lifetime in industrialized countries. Besides environmental ...factors also genetic factors have been identified as risk factors for SIDS. Notably, the mutation c.457dupG (p.Glu153Glyfs*17) in the TSPYL1 gene has been reported to cause autosomal recessive sudden infant death with dysgenesis of the testes syndrome (SIDDT) in an Old Order Amish community in Pennsylvania. The purpose of this study was to analyze whether variants of TSPYL1 are associated with the sudden infant death syndrome (SIDS) in the area of Europe from which the Amish descended. Mutation analysis of the entire TSPYL1 gene was performed in a cohort of 165 SIDS cases with mostly Swiss ethnic origin, in comparison to 163 German controls.
Eight known polymorphisms were detected, none of which was significantly associated with SIDS. One deceased girl was heterozygous for the hitherto unreported TSPYL1 variant c.106C>G (p.Leu36Val), and two affected girls were heterozygous for the rare known TSPYL1 variant rs140756663 (c.1098C>A, p.Phe366Leu). In addition, one deceased boy was heterozygous for the rare common silent nucleotide substitution c.718C>T (p.Leu240Leu, rs150144081), while one control was heterozygous for the rare silent nucleotide substitution rs56190632 (c.760C>T; p.Leu254Leu). In silico analyses predicted a likely non-pathogenic effect for p.Leu36Val and p.Phe366Leu, respectively, although protein features might be affected. The Amish founder mutation was not detected in the analyzed SIDS cases and controls. Mutations and polymorphisms in the TSPYL1 gene were not associated with SIDS in a cohort of 165 deceased Swiss infants.
ABSTRACT This study aimed to compare physical therapy with toys with dog-assisted therapy in the neuromotor development of 4-month-old infants with and without neuromotor alterations. This is a ...qualitative descriptive and observational study carried out with 10 infants, who were evaluated by the Alberta Infant Motor Scale, divided into Group 1 (G1) and Group 2 (G1), and subdivided into Toy Group (TG1 and TG2) and Dog Group (DG1 and DG2) for the performance of fortnightly interventions. By the Affordances in the Home Environment for Motor Development - Infant Scale, we assessed the opportunities present in the home environment. Qualitative data were analyzed using photos and videos. The presence of a dog in DG1 and DG2 resulted in a relaxed and fun environment, infants interested in touching the animal’s fur, alternating limb movements, eye contact, sound production, increased social interaction, and feeling of security. In TG1 and TG2, decrease in motivation was observed as well as the absence of sound production and eye contact by infants, and interest in touch restricted to toys that had different colors and sounds, with little agitation and motivation for motor skills in those groups. We concluded that the dog’s presence promoted better motor, social, affective, and cognitive results. Animal-assisted therapy can be an effective method to support conventional physical therapy for infants with delayed neuropsychomotor development.
RESUMEN El objetivo de este estudio fue comparar la fisioterapia con juguetes con la terapia asistida por perros en el desarrollo neuromotor de los lactantes de cuatro meses con y sin trastornos neuromotores. Se trata de una investigación cualitativa, descriptiva y observacional, realizada con 10 lactantes, quienes fueron evaluados por la escala motora infantil de Alberta (EMIA), divididos en grupo 1 (G1) y grupo 2 (G1), y subdivididos en grupo juguete (G1J y G2J) y el grupo con perro (G1P y G2P) para realizar las intervenciones quincenales. El cuestionario Affordances in the Home Environment for Motor Development - Infant Scale (AHEMD-IS) se aplicó para evaluar las oportunidades presentes en el entorno domiciliario. El análisis de los datos cualitativos se realizó a partir de fotografías y filmaciones. La presencia del perro en los grupos G1P y G2P resultó en un ambiente relajado y divertido, interés de los lactantes por tocar el pelaje del animal, alternancia de movimientos de las extremidades, contacto visual, emisión de sonidos, evolución en la interacción social y sensación de seguridad. En los grupos G1J y G2J hubo disminución de la motivación, ausencia de emisión de sonidos por parte de los lactantes y contacto visual e interés por el tacto restringido a los juguetes que tenían diferentes colores y sonidos, además de haber poca agitación y motivación para la motricidad en estos grupos. Se concluyó que la presencia del perro promovió mejores resultados motrices, sociales, afectivos y cognitivos. La terapia asistida por animales puede ser un método eficaz para ayudar en la fisioterapia convencional para los lactantes con retraso en el desarrollo neuropsicomotor.
RESUMO O objetivo deste trabalho foi comparar a fisioterapia com brinquedos com a terapia assistida por cães no desenvolvimento neuromotor de lactentes de quatro meses de idade com e sem alterações neuromotoras. Trata-se de pesquisa descritiva e observacional de caráter qualitativo, realizada com 10 lactentes, que foram avaliados pela escala motora infantil de Alberta (EMIA), divididos em grupo 1 (G1) e grupo 2 (G1) e subdivididos em grupo brinquedo (G1B e G2B) e grupo cão (G1C e G2C) para a realização das intervenções quinzenais. O questionário Affordances in the Home Environment for Motor Development - Infant Scale (AHEMD-IS) foi escolhido para avaliar as oportunidades presentes no ambiente domiciliar. A análise de dados qualitativos foi feita por meio de fotos e filmagens. A presença do cão nos grupos G1C e G2C resultou em um ambiente descontraído e divertido, interesse dos lactentes em tocar o pelo do animal, movimentos alternados de membros, contato visual, emissão de sons, evolução na interação social e sentimento de segurança. Nos grupos G1B e G2B, constatou-se diminuição da motivação, ausência de emissão de sons pelos lactentes e contato visual e interesse pelo toque restrito a brinquedos que tivessem diversas cores e sons, havendo pouca agitação e motivação para as habilidades motoras nesses grupos. Conclui-se que a presença do cão promoveu melhores resultados motores, sociais, afetivos e cognitivos. A terapia assistida por animais pode ser um método eficaz para auxiliar na fisioterapia convencional de lactentes com atraso no desenvolvimento neuropsicomotor.
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