Cynthia J. Curry

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome–associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Evaluation of mental retardation: Recommendations of a consensus conference

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

Maternal medications and environmental exposures as risk factors for gastroschisis

In a case-control study of gastroschisis, we evaluated the risks associated with mothers first-trimester use of medications and with hobby or occupational exposures for 110 cases and 220 controls without a birth defect. Mothers of cases and controls were age-matched. For hobby or occupational exposures, we found significantly elevated risks for high levels of solvents (odds ratio (OR) = 3.8; 95% confidence interval (CI) = 1.6-9.2) and for colorants (OR = 2.3; 95% CI = 1.3-4.0). For medications, we found significantly elevated risks for two strong cyclooxygenase inhibitors, aspirin (OR = 4.7; 95% CI = 1.2-18.1) and ibuprofen (OR = 4.0; 95% CI = 1.0-16.0), but not for acetaminophen, a weak cyclooxygenase inhibitor. Periconceptional exposure to X rays was also associated with gastroschisis (OR = 2.5; 95% CI = 1.2-5.5), but exposure to antibiotics, antinauseants, sulfonamides, or oral contraceptives was not. We also found elevated risks for two decongestants, pseudoephedrine (OR = 2.1; 95% CI = 0.8-5.5) and phenylpropanolamine (OR = 10.0; 95% CI = 1.2-85.6). For the group of all decongestants, including also oxymetazoline and ephedrine, the risk was significantly elevated (OR = 2.4; 95% CI = 1.0-5.4). Controlling in multivariate analyses for several demographic and pregnancy variables associated with gastroschisis in a previous analysis [Torfs et al. (1994) Teratology 50: 44-53] did not substantially change the level or direction of the associations. Most of these associations are for vasoactive substances, which supports a vascular hypothesis for the pathogenesis of gastroschisis.

WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta

This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C→A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.

Mutations in the TGF-β Repressor SKI Cause Shprintzen-Goldberg Syndrome with Aortic Aneurysm

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β–responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.

Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.

Macrocephaly‐Cutis marmorata telangiectatica congenita: A distinct disorder with developmental delay and connective tissue abnormalities

We describe 13 unrelated children with abnormalities of somatic growth, face, brain, and connective tissue including vasculature. Although the condition in these children falls under the general group of disorders known as cutis marmorata telangiectatica congenita (CMTC), the constellation of abnormalities appears to constitute a distinct and easily recognizable phenotype within this general group. In contrast to most children reported with CMTC, children in this subgroup have a high risk for neurologic abnormalities, including developmental delay, mental retardation, megalencephaly, and hydrocephalus. Early recognition of this condition is important for appropriate surveillance for known complications and parental counseling.

Hypospadias in California: Trends and Descriptive Epidemiology

Background The occurrence of hypospadias has been reported to be increasing. The objectives of this study were to extend the literature on the descriptive epidemiology of hypospadias and to determine whether its birth prevalence increased in California in recent years. We used actively ascertained, population-based data for which detailed clinical descriptions permitted careful phenotypic classifications. Methods We examined registry data on 5838 male live births and stillbirths that occurred in California from 1984 through 1997. To reduce pathogenic heterogeneity, cases were classified as mild, severe, or not otherwise specified based on the anatomic position of the urethral opening. We also classified cases as isolated or nonisolated based on the presence and type of accompanying malformations. We used multivariable Poisson regression analysis to examine time trends and risk factors. Results There was no evidence for an increase in prevalence of any of the case groups between 1989 and 1997. The adjusted relative risk (RR) for change in prevalence per year of isolated severe cases was 0.99 (95% confidence interval = 0.96–1.03). Adjusted RRs indicated increased risks for specific types of hypospadias with maternal non-Hispanic white race–ethnicity, higher education, older age, and nulliparity. Delivery before 37 weeks and multiple births tended either not to be associated with risk or to be associated with reduced risk. Lower birthweight was associated with increased risk for all case groups. Conclusions This study suggests that hypospadias prevalence has not been increasing in California in recent years. Differences by phenotype suggest that examining certain phenotypes separately could help to understand hypospadias etiology.

Schizencephaly: Heterogeneous etiologies in a population of 4 million California births

Schizencephaly is a rare congenital brain defect characterized by gray matter lined clefts of the cerebral mantle, frequently accompanied by other defects of the CNS such as absence of the corpus callosum. This study in a California population of >4 million births from 1985–2001 found a population prevalence of 1.54/100,000. Among 63 cases, there was an association with young parental age in isolated schizencephaly (RR 3.9 mothers; 5.8 fathers), which was also seen in mothers but not fathers of non‐isolated cases (RR 3.2). Monozygotic twins may also be at increased risk for schizencephaly (RR 2.1). One third of cases had a non‐CNS abnormality, over half of which could be classified as secondary to vascular disruption, including gastroschisis, bowel atresias, and amniotic band disruption sequence. Other apparent rare causes included chromosomal aneuploidy, non‐random associations, and unusual syndromes. Our observations suggest that schizencephaly has heterogeneous etiologies many of which are vascular disruptive in origin.