De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Diagnostic utility of microarray testing in pregnancy loss.

OBJECTIVES: To determine the frequency of clinically significant chromosomal abnormalities identified by chromosomal microarray in pregnancy losses at any gestational age and to compare microarray performance with that of traditional cytogenetic analysis when testing pregnancy losses. METHODS: Among 535 fetal demise specimens of any gestational age, clinical microarray-based comparative genomic hybridization (aCGH) was performed successfully on 515, and a subset of 107 specimens underwent additional single nucleotide polymorphism (SNP) analysis. RESULTS: Overall, clinically significant abnormalities were identified in 12.8% (64/499) of specimens referred with normal or unknown karyotypes. Detection rates were significantly higher with earlier gestational age. In the subset with normal karyotype, clinically significant abnormalities were identified in 6.9% (20/288). This detection rate did not vary significantly with gestational age, suggesting that, unlike aneuploidy, the contribution of submicroscopic chromosomal abnormalities to fetal demise does not vary with gestational age. In the 107 specimens that underwent aCGH and SNP analysis, seven cases (6.5%) had abnormalities of potential clinical significance detected by the SNP component, including female triploidy. aCGH failed to yield fetal results in 8.3%, which is an improvement over traditional cytogenetic analysis of fetal demise specimens. CONCLUSIONS: Both the provision of results in cases in which karyotype fails and the detection of abnormalities in the presence of a normal karyotype demonstrate the increased diagnostic utility of microarray in pregnancy loss. Thus, chromosomal microarray testing is a preferable, robust method of analyzing cases of pregnancy loss to better delineate possible genetic etiologies, regardless of gestational age.

Case series: 2q33.1 microdeletion syndrome--further delineation of the phenotype.

Recurrent deletions of 2q32q33 have recently been reported as a new microdeletion syndrome, clinical features of which include significant learning difficulties, growth retardation, dysmorphic features, thin and sparse hair, feeding difficulties, and cleft or high palate. Haploinsufficiency of one gene within the deleted region, SATB2, has been suggested to be responsible for most of the features of the syndrome. This article describes seven previously unreported patients with deletions at 2q33.1, all partially overlapping the previously described critical region for the 2q33.1 microdeletion syndrome. The deletions ranged in size from 35 kb to 10.4 Mb, with the smallest deletion entirely within the SATB2 gene. Patients demonstrated significant developmental delay and challenging behaviour, a particular behavioural phenotype that seems to be emerging with more reported patients with this condition. One patient in this cohort has a deletion entirely within SATB2 and has a cleft palate, whereas several patients with larger deletions have a high arched palate. In addition, one other patient has significant orthopaedic problems with ligamentous laxity. Interestingly, this patient has a deletion that lies just distal to SATB2. The orthopaedic problems have not been reported previously and are possibly an additional feature of this syndrome. Overall, this report provides further evidence that the SATB2 gene is the critical gene in this microdeletion syndrome. In addition, because the individuals in this study range in age from 3-19 years, these patients will help define the natural progression of the phenotype in patients with this microdeletion.

20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder.

Deletions of 20p are rare with the majority of reported cases involving individuals with 20p12 deletions associated with Alagille syndrome. We report on a child with a de novo mosaic 20p11 deletion who presents with panhypopituitarism; hypoplastic pituitary gland and ectopic posterior pituitary gland on MRI of the brain; cleft lip and palate; kyphosis with anterior beaking of L1 and L2 vertebral bodies; pulmonic stenosis; dysmorphic facial features including flat nasal bridge, hypoplastic premaxilla, hypotelorism, preauricular pit, and cupped ears; seizure disorder; variable muscle tone; and global developmental delay. Array comparative genomic hybridization revealed this deletion to be approximately 5.4 Mb in size, containing 35 genes. Previously, an infant with 20p11.22 deletion who had panhypopituitarism, craniofacial, and genital abnormalities was reported, but the precise parameters of that deletion are unavailable. Several other reported cases of 20p11 deletions also have phenotypic overlap with our case. The similarities in clinical features of these patients suggest that the genes at 20p11 have a critical role in development of midline brain structures.

The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications.

Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations.

BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3.

Acute otitis media in children.

Acute otitis media (AOM) is the most common reason parents bring children into the primary care physician's office. It is diagnosed by clinical symptoms of otalgia and often fever and irritability and by clinical otoscopy. Organisms common to the nasopharynx usually cause AOM. Many episodes of AOM resolve spontaneously. Because it is uncertain how many and which children will resolve without therapy, it is reasonable to treat all children with AOM with antibiotics. The first choice of antibiotics is amoxicillin. Other choices rest on a variety of factors.

Heart disease in women. Gender-specific statistics and prevention strategies for a population at risk.

For decades, coronary artery disease (CAD) was thought to be primarily a disease of middle-aged men, in whom most research was conducted. But CAD afflicts a diverse patient population, and a major subset of those patients--women--present special diagnostic and therapeutic challenges for the primary care physician. In this article, Dr Rosenfeld provides an overview of CAD in women and discusses its causes and risk factors, prevention strategies, and gender-specific characteristics. She also examines the effect of gender-biased research on the views of both patients and physicians.

Abdominal trauma in pregnancy. When is fetal monitoring necessary?

The type and duration of observation and monitoring of mother and fetus after abdominal trauma are dependent on gestational age and severity of trauma. Fetal monitoring is usually not required when the fetus is not viable; the primary consideration is the safety of the mother. When the fetus is viable, 24-hour inpatient fetal monitoring is indicated in cases of major trauma, even when no symptoms of injury are obvious.

Pregnancy in women over 35. Risks for mother and baby.

Because many women today are either delaying their first pregnancy or continuing to have babies later in life, the risks to older mothers are becoming increasingly important. However, intensive prenatal care and monitoring have enhanced the likelihood of a successful outcome. In this article, Dr Rosenfeld reviews studies of pregnancy in older women and suggests ways that primary care physicians can be involved in advising and caring for these patients.

Doesn't everyone grieve in the abortion choice?

PIP: Brown, Elkins, and Larson's article on prolonged grieving after induced abortion properly alerts physicians to the need for vigilance to emotional difficulties following this procedure. However, the authors appear to have an implicit political agenda in publishing their material, and the absence of scientific method in the presentation of this material is reckless given the political volatility surrounding the abortion issue. The article is based on an analysis of 61 letters solicited by the pastor of a Protestant church in Florida known for its anti-abortion activities; only negative experiences were sought. Cited are long-term negative sequelae such as anger, loss, depression, masking of emotion, regret, shame, guilt, fantasizing, and suicidal ideation. It is impossible for the authors to make psychiatric diagnoses on the basis of letters alone. More importantly, these same reactions can be found, to an even greater extent, among women suffering forced continuation of an unwanted pregnancy and subsequent nonvoluntary parenthood. Feelings of guilt and loss can be expected both among women who choose to abort and those who opt to continue with an unplanned pregnancy. The very fact that abortion is legal in the US allows physicians to help those women who do experience emotional difficulties after the procedure.^ieng

The effect of epidural anesthesia on the length of labor.

BACKGROUND: Epidural anesthesia, although effective, has been associated with changing the course of labor. Previous studies have been criticized for not pinpointing the factors determining the use of epidural anesthesia. The purpose of this study was to determine the effect of epidural anesthesia use on the course of labor. METHODS: A retrospective chart review of 224 women who gave birth from July 1, 1993, to June 30, 1994, was completed in a small-town family practice. The time frame included 6 months before and after the initiation of Tenncare, a state-funded health insurance plan designed to serve the uninsured and those previously served by Medicaid in Tennessee. RESULTS: The rate of epidural anesthesia use in this study population fell sharply after January 1, 1994, the start date for Tenncare. Epidural anesthesia by women in this study was found to increase the average length of the second stage of labor by 38 minutes for primiparas and 23 minutes for multiparas. CONCLUSIONS: The average length of the second stage of labor is significantly longer for women who receive epidural anesthesia. The rate of epidural anesthesia use in this study population was strongly influenced by a change in health-care financing.

Factors related to planned and unplanned pregnancies.

BACKGROUND: Given the efficacy of most contraceptive options, it is of concern that most pregnancies in the United States are unplanned. Besides reducing the woman's and family's preparedness for parenting, unplanned pregnancies are at higher risk for inadequate prenatal care, perinatal morbidity, and significant postnatal problems. Little is known about the factors responsible for the high rates of unplanned pregnancy. METHODS: One hundred ten pregnant women were surveyed to examine factors relating contraception to unplanned pregnancy. RESULTS: Sixty-five percent of pregnancies were unplanned. There was a statistically significant association between having unplanned pregnancies and being single or divorced. Women who had planned their pregnancies tended to be more satisfied with contraceptives. In sexual encounters, women with unplanned pregnancies were more likely to use no contraception or to practice "withdrawal" or use condoms rather than hormonal contraception; to be influenced by their partner regarding birth control use; and to forget to use contraception. CONCLUSIONS: All women of childbearing age who are sexually active can benefit from planning pregnancies. Counseling that accesses a woman's expectations regarding birth control, followed by a careful explanation of the side effects of a contraception choice, may reduce the rate of unplanned pregnancy. Counselling the male partner or sexually active men in contraceptive options may be equally important. Understanding factors that result in satisfaction with contraception may reduce unplanned pregnancies.

PIP: In the summers of 1994 and 1995 in northeastern Tennessee, 110 pregnant women 16-37 years old were interviewed either before or after their prenatal care appointment at an outpatient family practice clinic in Bristol. The researchers aimed to identify factors associated with planned and unplanned pregnancies. 39 (35%) women had planned their pregnancy while the remaining 71 (65%) women did not. Divorced or never married women were more likely to have an unplanned pregnancy than a planned pregnancy (47% vs. 19%; p 0.01). Women with an unplanned pregnancy were more likely to have been using contraception at time of conception than women with a planned pregnancy (23% vs. 3%). They were also more likely to use no contraception or to practice withdrawal before the index pregnancy than women with a planned pregnancy (31% vs. 13%; p 0.05). All the women in both groups had no problem with availability of their choice of family planning method. Women with an unplanned pregnancy were much more likely than those with a planned pregnancy to be influenced by their partner in terms of contraceptive choice (37% vs. 19%; p = 0.04). Women with a planned pregnancy were more likely to be satisfied or very satisfied with their contraception than those with an unplanned pregnancy (62% vs. 43%). The differences in satisfaction only approached statistical significance, however (p = 0.065). Based on these findings, the family practice researchers suggested that, in order to reduce unplanned pregnancies, clinicians should provide women counseling on their contraception expectations and a careful explanation of the side effects of their contraceptive choice. Male partners or sexually active men should also receive counseling about contraceptive options. Another important step is further research to better understand factors that contribute to satisfaction with contraception.

Women's satisfaction with birth control.

BACKGROUND: Contraception is a major component of preventive health care for women. There are indications that women are not satisfied with the methods of birth control currently available. Dissatisfaction with contraceptive methods may lead to unplanned pregnancies. METHODS: Adult women visiting the family health center over a 1-year period were invited to participate in a research interview. Questions were asked about demographic variables and the women's use of, and their satisfaction with, contraceptive methods. RESULTS: Many women were displeased with the present methods of birth control. This is reflected in the numerous methods used by each woman, and by frequent use of permanent sterilization as a contraceptive method. Women were as dissatisfied with oral contraceptives as they were with the less efficacious methods such as condoms, foams, gels, and rhythm. The only methods that had a greater than 70% satisfaction rate were tubal ligations and partner's vasectomies. CONCLUSIONS: There is significant dissatisfaction with the methods of contraception currently available. Increased patient-physician discussion and education may improve satisfaction with birth control methods now used. New methods of contraception may be needed to prevent unplanned pregnancies.

Comparison of female and male graduates of southern Appalachian family practice residencies.

PURPOSE: One aim of Southern Appalachian family practice residencies is to produce graduates for surrounding physician-needy areas. Some evidence suggests that women are less likely to go to rural areas and that they practice differently than men. This study investigated the practice patterns and location of Appalachian family practice residency female and male graduates. METHODS: Surveys were sent to graduates of seven family practice residencies from 1984 to 1994 in the Southern Appalachian area to determine practice patterns, locations, and reasons for choosing practices. RESULTS: Women were more likely than men to be single and not to have children. More women worked part-time. Women's and men's practice patterns and characteristics were similar except that women were more likely to provide prenatal care and do vaginal deliveries. Women in similar percentages practiced in small towns, and a greater percentage of women practiced in rural areas with populations of less than 2,500. CONCLUSIONS: Female family practice residency graduates from Appalachian residencies are fulfilling the purposes of their residencies as well as male graduates, although more of them are working part-time.

Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly.

Microduplications of the Sotos syndrome region containing NSD1 on 5q35 have recently been proposed to cause a syndrome of microcephaly, short stature and developmental delay. To further characterize this emerging syndrome, we report the clinical details of 12 individuals from 8 families found to have interstitial duplications involving NSD1, ranging in size from 370 kb to 3.7 Mb. All individuals are microcephalic, and height and childhood weight range from below average to severely restricted. Mild-to-moderate learning disabilities and/or developmental delay are present in all individuals, including carrier family members of probands; dysmorphic features and digital anomalies are present in a majority. Craniosynostosis is present in the individual with the largest duplication, though the duplication does not include MSX2, mutations of which can cause craniosynostosis, on 5q35.2. A comparison of the smallest duplication in our cohort that includes the entire NSD1 gene to the individual with the largest duplication that only partially overlaps NSD1 suggests that whole-gene duplication of NSD1 in and of itself may be sufficient to cause the abnormal growth parameters seen in these patients. NSD1 duplications may therefore be added to a growing list of copy number variations for which deletion and duplication of specific genes have contrasting effects on body development.

Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions.

TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1's role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.