De novo unbalanced translocations have a complex history/aetiology.

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin.

Risk assessment models in genetics clinic for array comparative genomic hybridization: Clinical information can be used to predict the likelihood of an abnormal result in patients.

Array comparative genomic hybridization (aCGH) testing can diagnose chromosomal microdeletions and duplications too small to be detected by conventional cytogenetic techniques. We need to consider which patients are more likely to receive a diagnosis from aCGH testing versus patients that have lower likelihood and may benefit from broader genome wide scanning. We retrospectively reviewed charts of a population of 200 patients, 117 boys and 83 girls, who underwent aCGH testing in Genetics Clinic at Rhode Island hospital between 1 January/2008 and 31 December 2010.

A novel familial 11p15.4 microduplication associated with intellectual disability, dysmorphic features, and obesity with involvement of the ZNF214 gene.

We evaluated a patient with mild intellectual disability, obesity, overgrowth, and dysmorphic features. Array comparative genomic hybridization (aCGH) analysis showed a single copy number increase of a BAC clone in the 11p15.4 region.

Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature.

Mycophenolate mofetil (MMF) (CellCept) is an immunosuppressant drug that is teratogenic in rats and rabbits. Reports of malformations in 13 offspring of women exposed to MMF in pregnancy raise concern that MMF is also a human teratogen. We report an additional child with malformations following prenatal exposure to MMF and review the other 13 reports.

Clinical significance of chimerism.

Twins have been previously classified as either monozygotic or dizygotic. In recent years, fascinating, non-traditional mechanisms of twinning have been uncovered. We define chimerism versus mosaicism, touch on chimerism in the animal world, and explain timing of chimerism in humans.

Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival.

Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump (ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations.

A novel mutation of the fibrillin-1 gene in a newborn with severe Marfan syndrome.

Marfan syndrome in the neonatal age represents a severe early and commonly lethal manifestation of Marfan syndrome, which is caused by mutations in the gene encoding fibrillin-1 (FBN1). Here, we report a newborn with severe Marfan syndrome and a novel mutation involving cysteine substitution within one of the epidermal growth factor-like domains of FBN1.

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD).

Major congenital anomalies place extremely low birth weight infants at higher risk for poor growth and developmental outcomes.

Background: Studies of growth and neurodevelopmental impairment in extremely low birth weight infants often exclude infants with major congenital anomalies; thus, there are few outcome data available on these infants.

Objectives: The purpose of this work was to compare growth and neurodevelopmental outcomes of extremely low birth weight infants with major anomalies to extremely low birth weight infants without these findings. It was hypothesized that infants with severe anomalies would have worse growth, neurodevelopmental, and survival outcomes.

Microcephaly syndromes.

The objective of this article is to review microcephaly from a genetics point of view, especially with regard to the process of identification of syndromes in which small head circumference occurs. Microcephaly can be due to either genetic or environmental causes. It can be the only positive finding or may be part of a syndrome of congenital anomalies.

Bilateral semilunar valve dysplasia in a patient with inverted duplication 2p25-22.

Here we report a patient with partial trisomy 2p and congenital dysplasia of the semilunar valves. To our knowledge, this is the first case of 2p duplication with developmental defects of both semilunar valves and suggests that genes on this region contribute to the formation of the semilunar valves.

Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28.

Objective: Our goal was to describe the neurologic and clinical features of affected males from families with X-linked patterns of severe mental retardation, hypotonia, recurrent respiratory infection, and microduplication of Xq28 that consistently includes the MECP2 (methyl-CpG binding protein 2) gene.

Study Design: To identify duplications, multiplex ligation-dependent probe amplification of the MECP2 gene was performed on male probands from families with X-linked mental retardation. The males either had linkage to Xq28 or had a phenotype consistent with previous reports involving Xq28 functional disomy.

Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy.

Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2alpha kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K(+) channel subunit Kir6.2. We sequenced the gene encoding Kir6.

Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia.

Adolescents and genetic testing: what do they think about it?

Purpose: To examine adolescents' attitudes toward screening for hereditary disorders.

Methods: A survey was distributed among 672 students in grades 10 to 12 attending a public suburban high school. The first part of the survey consisted of information about three diseases: familial breast cancer, Tay-Sachs disease, and hypercholesterolemia.

Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14.

Background: Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome.

Methods And Results: Fifteen families were identified with multiple members with TAAs/dissections.

Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome.

We have analyzed the survival motor neuron gene (SMN1) dosage in 100 parents of children with homozygous SMN1 deletions. Of these parents, 96 (96%) demonstrated the expected one-copy SMN1 carrier genotype. However, four parents (4%) were observed to have a normal two-copy SMN1 dosage.

Distal 5q trisomy resulting from an X;5 translocation detected by chromosome painting.

We describe the case of a 13-year-old girl with an apparently de novo unbalanced translocation resulting in the presence of additional chromosomal material on the short arm of one X chromosome, which was detected by conventional G-banding studies. Fluorescence in situ hybridization (FISH) using the Chromoprobe Multiprobe-M protocol confirmed that the additional chromosomal material originated from chromosome 5. The karyotype of this patient is now established to be 46,X,der(X) t(X;5)(p22.