A novel six3 mutation segregates with holoprosencephaly in a large family

Holoprosencephaly is the most common structural malformation of the forebrain in humans and has a complex etiology including chromosomal aberrations, single gene mutations and environmental components. Here we present the pertinent clinical findings among members of an unusually large kindred ascertained over 15 years ago following the evaluation and subsequent genetic work-up of a female infant with congenital anomalies. A genome-wide scan and linkage analysis showed only suggestive evidence of linkage to markers on chromosome 2 among the most likely of several pedigree interpretations. We now report that a novel missense mutation in the SIX3 holopro- sencephaly gene is the likely cause in this family. Molecular genetic analysis and/or clinical characterization now show that at least 15 members of this family are presumed SIX3 mutation gene carriers, with clinical manifestations ranging from pheno- typically normal adults (non-penetrance) to alobar holoprosen- cephaly incompatible with postnatal life. This particular family represents a seminal example of the variable manifestations of gene mutations in holoprosencephaly and difficulties encountered in their elucidation.Fil: Solomon, Benjamin D.. National Institutes of Health; Estados UnidosFil: Lacbawan, Felicitas. National Institutes of Health; Estados Unidos. State University of New York; Estados UnidosFil: Jain, Mahim. National Institutes of Health; Estados UnidosFil: Domene, Sabina. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Roessler, Erich. National Institutes of Health; Estados UnidosFil: Moore, Cynthia. Indiana University School of Medicine; Estados UnidosFil: Dobyns, William B.. University of Chicago; Estados UnidosFil: Muenke, Maximilian. National Institutes of Health; Estados Unido

Medical genetics and genomic medicine in the United States. Part 2: Reproductive genetics, newborn screening, genetic counseling, training, and registries

eview of genetics in the United States with emphasis on the prenatal, metabolic, genetic counseling, and training aspects of the field

The Enigma of Number: Why Children Find the Meanings of Even Small Number Words Hard to Learn and How We Can Help Them Do Better

Although number words are common in everyday speech, learning their meanings is an arduous, drawn-out process for most children, and the source of this delay has long been the subject of inquiry. Children begin by identifying the few small numerosities that can be named without counting, and this has prompted further debate over whether there is a specific, capacity-limited system for representing these small sets, or whether smaller and larger sets are both represented by the same system. Here we present a formal, computational analysis of number learning that offers a possible solution to both puzzles. This analysis indicates that once the environment and the representational demands of the task of learning to identify sets are taken into consideration, a continuous system for learning, representing and discriminating set-sizes can give rise to effective discontinuities in processing. At the same time, our simulations illustrate how typical prenominal linguistic constructions (“there are three balls”) structure information in a way that is largely unhelpful for discrimination learning, while suggesting that postnominal constructions (“balls, there are three”) will facilitate such learning. A training-experiment with three-year olds confirms these predictions, demonstrating that rapid, significant gains in numerical understanding and competence are possible given appropriately structured postnominal input. Our simulations and results reveal how discrimination learning tunes children's systems for representing small sets, and how its capacity-limits result naturally out of a mixture of the learning environment and the increasingly complex task of discriminating and representing ever-larger number sets. They also explain why children benefit so little from the training that parents and educators usually provide. Given the efficacy of our intervention, the ease with which it can be implemented, and the large body of research showing how early numerical ability predicts later educational outcomes, this simple discovery may have far-reaching consequences

A two-locus genetic interaction between LPHN3 and 11q predicts ADHD severity and long-term outcome

The severity of attention-deficit/hyperactivity disorder (ADHD) symptoms is a major predictor of long-term ADHD outcome. To investigate if two-locus interactions might predict ADHD severity, we studied a sample of 1341 individuals from families clustering ADHD, using the Vanderbilt Assessment Scale for Parents. Latent class cluster analysis was used to construct symptom profiles and classify ADHD severity. Single nucleotide polymorphisms (SNPs) spanning ADHD-linked chromosomal regions on chromosomes 4, 5, 10, 11, 12 and 17 were genotyped. SNPs associated with ADHD severity were identified and potential two-locus genetic interactions were tested. We found that SNPs within the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 not only to increase the risk of developing ADHD but also to increase ADHD severity. All these genes are identified to have a major role in shaping both brain development and function. These findings demonstrate that genetic interactions may predict the severity of ADHD, which in turn may predict long-term ADHD outcome

BOC is a modifier gene in holoprosencephaly

Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a complex etiology. Heterozygous, loss‐of‐function mutations in the sonic hedgehog (SHH) pathway are associated with HPE. However, mutation carriers display highly variable clinical presentation, leading to an “autosomal dominant with modifier” model, in which the penetrance and expressivity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers have not been identified. Boc encodes a SHH coreceptor and is a silent HPE modifier gene in mice. Here, we report the identification of missense BOC variants in HPE patients. Consistent with these alleles functioning as HPE modifiers, individual variant BOC proteins had either loss‐ or gain‐of‐function properties in cell‐based SHH signaling assays. Therefore, in addition to heterozygous loss‐of‐function mutations in specific SHH pathway genes and an ill‐defined environmental component, our findings identify a third variable in HPE: low‐frequency modifier genes, BOC being the first identified.Holoprosencephaly (HPE), the most developmental common defect of the forebrain, is best explained by a “mutation with modifier” model. However, HPE modifier genes have not been identified. Here, we report HPE‐associated missense variants within the Hedgehog coreceptor BOC (arrows). Functional analyses of these variants, along with previous work in mouse models, are consistent with the conclusion that these variants act as phenotypic modifiers of a driver mutation or environmental insult.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138902/1/humu23286-sup-0001-text.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138902/2/humu23286_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138902/3/humu23286.pd

Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?

published_or_final_versio

A Korean Family with the Muenke Syndrome

The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members

A Case of Pfeiffer Syndrome

Pfeiffer Syndrome is as rare as Apert syndrome in the Western population. This condition is very rare in the Asian population and has not been previously reported in Korea. The authors report with a review of literature the case of a newborn baby with Pfeiffer syndrome, manifested by bicoronal craniosynostosis, broad thumbs, and big toes. The infant also had bilateral syndactyly of the fingers and toes, mild proptosis, choanal hypoplasia and maxillary hypoplasia