Parental balanced reciprocal translocations can result in partial aneuploidies in the offspring due to unbalanced meiotic segregation during gametogenesis. Herein, we report the phenotypic and molecular cytogenetic characterization of a 2 years and 4 months old female child with partial trisomy 7q22 → qter. This is the first such reported case resulting from a parental balanced translocation involving the long arms of chromosomes 7 and 14. The phenotype of the proband was compared with that of previously reported cases of trisomy 7q21 → qter or 7q22 → qter resulting from parental balanced translocations.

Recently, bi‐allelic mutations in cytosolic isoleucyl‐ tRNA synthetase ( IARS ) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole‐exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper‐elasticity, and hypervitaminosis D.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras‐mitogen‐activated protein kinase (RAS‐MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month‐old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS‐MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS ‐associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis. © 2015 Wiley Periodicals, Inc.

Turner syndrome (TS) is caused by the partial or complete loss of the second sex chromosome in females and affects 1 in 2500 live female births. Thirty percent of women with non-mosaic classic TS (45,X) have bicuspid aortic valve (BAV), as compared to 1-2% of individuals in the general population. BAV and aortic coarctation have been associated with loss of the p arm of the X chromosome in TS. Importantly, the presence of cardiac anomalies in TS greatly increases the risk of cardiac related death in women with TS who pursue donor egg pregnancy. Gene expression profiling studies may identify specific genes on the X chromosome associated with BAV, or may highlight ongoing differences in gene transcription related to the presence of BAV. Gene expression profiling analysis. Sixteen women with 45,X detected on peripheral karyotype in 50 cells underwent DNA expression array profiling of peripheral blood lymphocytes using Affymetrix GeneChip Human Genome U133 Plus 2.0 Array as part of the IRB approved NICHD protocol "Turner Syndrome: Genotype and Phenotype." All women underwent cardiac MRI to accurately access aortic valve anatomy and all 16 had unambiguous cardiac MRI results. Eight women had BAV and eight women had tricuspid aortic valve (TAV). Analysis comparing TS with TAV and TS with BAV gene expression was performed with Partek Genomics Suite, using a 1-way ANOVA test. Comparing TS with BAV and TS with TAV, 2747 genes show a significant difference in expression of 1.2 fold or greater (p<0.05) and 155 genes were differentially expressed with p-value less than 0.001. Genes with greater than a 2 fold difference are enriched for immunoglobulin genes, with 11 immunoglobulin (Ig) genes showing greater than 2 fold up-regulation in BAV versus TAV (of 67 genes). CD38, a gene encoding for a cell surface marker, is up-regulated 1.9 fold in BAV versus TAV (p=0.0011). There are differences in gene expression comparing TS with BAV versus TAV. It is unclear why expression of Ig genes would be up-regulated with BAV; however, this finding may have potential as a biomarker in TS for BAV through measurement of quantitative Igs or Ig light chain assays. Additionally, flow cytometry may detect different levels of CD-38 expression, another possible biomarker. These findings require confirmation using a different expression profiling modality. Further study is needed to explore whether these or possibly other biomarkers suggested by transcriptomic data, may be useful clinically in TS.

Turner syndrome (TS) occurs in 1 in 2500 live female births and includes a spectrum of phenotypic findings, from more severely affected infants with congenital heart disease and lymphedema to adults with short stature and gonadal dysgenesis. In classic 45,X TS, two-thirds of patients are missing the paternal sex chromosome and carry only the maternal X (Xm), while the other one-third carry a paternal X (Xp). This is an important distinction as some aspects of the TS phenotype are affected by which parental X is inherited. X imprinting may explain some sexually dimorphic traits, and these traits would be predicted to vary in TS based on which X is inherited. Gene expression profiling studies may highlight which genes on the X are potentially imprinted or what genes throughout the genome are differentially expressed, helping to explain phenotypic differences. Gene expression profiling analysis. Twenty-six women with 45,X detected on peripheral karyotype in 50 cells underwent DNA expression array profiling of peripheral blood lymphocytes using Affymetrix GeneChip Human Genome U133 Plus 2.0 Array as part of the IRB approved NICHD protocol "Turner Syndrome: Genotype and Phenotype." Ten women inherited their X chromosome from their father (Xp) and 16 women inherited their X chromosome from their mother (Xm). Analysis comparing TS Xp and TS Xm gene expression was performed with Partek Genomics Suite, using a 1-way ANOVA test. Comparing inheritance of the Xm versus Xp in TS, 3443 genes show differences in expression, with p-value less than 0.05, and 63 genes show a highly significant difference (p<0.001). One transcript for a non-coding (nc) RNA (probe ID 242299_at) on the X chromosome was expressed 1.53 fold greater in TS Xp versus Xm (p=0.028). Significant differences in gene expression between Xm and Xp groups do exist. NcRNA 242299_at is located within the X-inactivation center (XIC), suggesting a possible regulatory role in expression of XIST, the primary ncRNA responsible for X inactivation. NcRNAs generally play a major role in transcription regulation throughout the genome and therefore, are important candidates for explaining phenotypic differences in TS. These findings require confirmation using a different expression profiling modality. Further study is needed to understand the molecular actions of ncRNA 242299_at and whether it may play a role in the XIC.

Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the Fibroblast Growth Factor Receptor3 ( FGFR3 ) gene. Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. Although talocalcaneal coalition is the most common tarsal coalition in the general population, it has never previously been reported in a patient with Muenke syndrome. We present a 7‐year‐old female patient with Muenke syndrome and symptomatic talocalcaneal coalition. She presented at the age of 7 with limping, tenderness and pain in her right foot following a fall and strain of her right foot. She was treated with ibuprofen, shoe inserts, a CAM walker boot, and stretching exercises without much improvement in symptoms. A computed tomography (CT) scan revealed bilateral talocalcaneal coalitions involving the middle facet. She underwent resection of the talocalcaneal coalitions, remaining pain‐free post‐operatively with an improvement in her range of motion, gait, and mobility. This report expands the phenotype of tarsal coalition in Muenke syndrome to include talocalcaneal coalition. A literature review revealed a high incidence of tarsal coalition in all FGFR related craniosynostosis syndromes when compared to the general population, a difference that is statistically significant. The most common articulation involved in all syndromic craniosynostoses associated with FGFR mutations is the calcaneocuboid articulation. © 2013 Wiley Periodicals, Inc.

Patients with a combination of holoprosencephaly and polydactyly, but with apparently normal chromosomes, may be clinically diagnosed with holoprosencephaly-polydactyly syndrome (HPS), also termed pseudotrisomy 13. However, the criteria for HPS have been controversial since the advent of the diagnostic term, and a clear understanding of the condition lacks definitive delineation. We review the historical and current perspectives on the condition and analyze findings in 40 patients with apparent HPS, including cases from the literature and two previously unreported patients. Overall, our analysis suggests previously unrecognized trends in patients diagnosed with HPS. Specifically, there appears to be a higher prevalence of visceral anomalies, most significantly cardiac and genitourinary, but also with increased gastrointestinal, pulmonary, adrenal, skeletal, and renal abnormalities, in patients with HPS. Although these visceral anomalies may not be essential for the identification of HPS, clinicians should be aware of the presence of such characteristics in these patients to optimize management and help establish etiologies.

BACKGROUNDHoloprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes.METHODSWe report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups.RESULTSWe detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues).CONCLUSIONSFrom these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012.

Holoprosencephaly is the most common malformation of the forebrain and typically results in severe neurocognitive impairment with accompanying midline facial anomalies. Holoprosencephaly is heterogeneous and may be caused by chromosome aberrations or environmental factors, occur in the context of a syndrome or be due to heterozygous mutations in over 10 identified genes. The presence of these mutations may result in an extremely wide spectrum of severity, ranging from brain malformations incompatible with life to individuals with normal brain findings and subtle midline facial differences. Typically, clinicians regard intellectual disability as a sign that a parent or relative of a severely affected patient may be a mildly affected mutation ‘carrier’ with what is termed microform holoprosencephaly. Here we present 5 patients with clear phenotypic signs of microform holoprosencephaly, all of whom have evidence of above-average intellectual function. In 4 of these 5 individuals, the molecular cause of holoprosencephaly has been identified and includes mutations affecting SHH, SIX3, GLI2, and FGF8. This report expands the phenotypic spectrum of holoprosencephaly and is important in the counseling of patient and affected families.

Although Muenke syndrome is the most common syndromic form of craniosynostosis, the frequency of oral and palatal anomalies including high-arched palate, cleft lip with or without cleft palate has not been documented in a patient series of Muenke syndrome to date. Further, to our knowledge, cleft lip and palate has not been reported yet in a patient withMuenke syndrome (a previous patient with isolated cleft palate has been reported). This study sought to evaluate the frequency of palatal anomalies in patients with Muenke syndrome through both a retrospective investigation and literature review. A total of 21 patients who met criteria for this study were included in the retrospective review. Fifteen patients (71%) had a structural anomaly of the palate. Cleft lip and palate was present in 1 patient (5%). Other palatal findings included high-arched hard palate in 14 patients (67%). Individuals with Muenke syndrome have the lowest incidence of cleft palate among the most common craniosynostosis syndromes. However, high-arched palate in Muenke syndrome is common and may warrant clinical attention, as these individuals are more susceptible to recurrent chronic otitis media with effusion, dental malocclusion, and hearing loss.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.