Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

Short-term memory deficits in carrier females with KDM5C mutations.

We present the cognitive abilities of females from five families who carry a mutation in a gene (KDM5C, formerly JARIDIC or SMCX) in Xp 11.2 that encodes a transcriptional regulator with histone demethylase activity that is specific for dimethylated and trimethylated H3K4. In this report, the cognitive abilities of females who carry KDMSC mutations are compared to females who carry mutations in other genes known to cause X-linked intellectual and developmental disability (XLIDD) conditions. The KDM5C mutation carriers had higher mean scores on the abstract/visual and quantitative sections of the Stanford-Binet Intelligence Scale: Fourth Edition and lower mean short term memory scores. Implications for counseling are presented.

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome.

BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio-facio-cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild-type BRAF but is less strongly activating than the cancer-associated p.V600E mutation.

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. RESULTS: In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (< 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. CONCLUSION: We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome.

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Escape of the yolk sac: a hypothesis to explain the embryogenesis of gastroschisis.

Gastroschisis is a significant birth defect that in many countries has shown an increased prevalence in recent decades, and the change has affected primarily younger mothers. Despite numerous epidemiological studies no other consistent associated risk factor has been identified. In this paper we review the five main theories related to the pathogenesis of this malformation and outline the reasons why we think none fully explains the embryogenesis of gastroschisis. We briefly present some clinical observations we have made that we consider germane to the pathogenesis and outline a hypothesis that we think can account for the origins of this malformation. Our proposal is that the determining defect in gastroschisis is failure of the yolk sac and related vitelline structures to be incorporated into the umbilical stalk. Otherwise, ventral closure of the lateral abdominal walls occurs normally, thus orphaning the vitelline duct and yolk sac outside both the main body stalk and the abdominal wall. Thus, in addition to the umbilicus, the abdominal wall has a separate perforation through which the midpoint of the gut is attached to the exteriorized vitelline structures. This connection through the ventral wall prevents normal egress of the gut into the umbilical cord during the second month of development and acts as the egress point for the gut resulting in gastroschisis.

Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia.

BACKGROUND: Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively more common causes of XLMR with a frequency of approximately 3% in males with proven or probable XLMR. The JARID1C protein functions as a histone 3 lysine 4 (H3K4) demethylase and is involved in the demethylation of H3K4me3 and H3K4me2. METHODS: Mutation analysis of the JARID1C gene was conducted in the following cohorts: probands from 23 XLMR families linked to Xp11.2, 92 males with mental retardation and short stature, and 172 probands from small XLMR families with no linkage information. RESULTS: Four novel mutations consisting of two missense mutations, p.A77T and p.V504M, and two frame shift mutations, p.E468fsX2 and p.R1481fsX9, were identified in males with mental retardation. Two of the mutations, p.V504M and p.E468fsX2, are located in the JmjC domain of the JARID1C gene where no previous mutations have been reported. Additional studies showed that the missense mutation, p.V504M, was a de novo event on the grandpaternal X chromosome of the family. Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%). The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%). CONCLUSION: Based on the clinical observations, male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene.

Increased platelet arachidonic acid metabolism in diabetes mellitus.

Platelets obtained from some diabetic patients show enhanced in vitro platelet aggregation. This study sought to determine if platelet obtained from insulin-dependent diabetic subjects synthesize increased quantities of the labile aggregating substance, thromboxane A2 (TXA2), and if it may play a role in the enhanced platelet aggregation. Arachidonic acid (1 mM)-stimulated TXA2 synthesis, as determined via radioimmunoassay of its stable metabolite TXB2, was significantly greater (P less than 0.01, N = 12) in platelet-rich plasma obtained from diabetics compared with matched controls. Arachidonic acid-stimulated TXB2 synthesis in the diabetic platelet-rich plasma was positively correlated with the ambient fasting plasma glucose (r = 0.61, P less than 0.02, N = 15). Platelet aggregation induced by arachidonic acid (0.4-0.8 mM) was inhibited significantly less by 13-azaprostanoic acid (P less than 0.04, N = 14), a competitive antagonist of the actions of prostaglandin H2 or TXA2 on platelets, compared with matched controls. The results support the notion that platelets obtained from some insulin-dependent diabetic subjects manifest increased synthesis of TXA2, which may contribute to the enhanced platelet aggregation.

TNF(alpha) modulation of visceral and spinal sensory processing.

The cytokine tumor necrosis factor(alpha) (TNF(alpha)) is associated with a constellation of physiological and behavioral characteristics that follow in response to infection such as fever, fatigue, listlessness, loss of appetite, malaise, and tactile hypersensitivity. These responses are examples of central nervous system (CNS) functions modified by the activated immune system. Our studies have focused on the involvement of TNF(alpha) in CNS control of gastrointestinal function and "visceral malaise". We have demonstrated that TNF(alpha) can elicit gastric stasis in a dose-dependent fashion via its interaction with vago-vagal neurocircuitry in the brainstem. Sensory elements of the vago-vagal reflex circuit (i.e., neurons of the solitary tract [NST] and area postrema [AP]) are activated by exposure to TNF(alpha), while the efferent elements (i.e., dorsal motor neurons of the vagus [DMN]) cause gastroinhibition. Transient exposure to low doses of TNF(alpha) cause potentiated (exaggerated) NST responses to stimulation. Subsequent studies suggest that TNF(alpha) presynaptically modulates the release of glutamate from primary afferents to the NST. Using immunohistochemical studies, we have observed the constitutive expression of the TNFR1 receptor on central vagal afferents and spinal trigeminal afferents in the medulla, as well as on cells and afferent fibers within the dorsal root ganglia and within laminae I and II of the dorsal horn throughout the spinal cord. The constitutive presence of these receptors on these afferents may explain why inflammatory or infectious processes that generate TNF(alpha) can disrupt gastrointestinal functions and cause tactile hypersensitivity. These receptors may also play a critical role in the chronic allodynia and hyper-reflexia observed after spinal cord injury or peripheral nerve damage.

Characterization of neurons of the nucleus tractus solitarius pars centralis.

Esophageal sensory afferent inputs terminate principally in the central subnucleus of the tractus solitarius (cNTS). Neurons of the cNTS comprise two major neurochemical subpopulations. One contains neurons that are nitric oxide synthase (NOS) immunoreactive (-IR) while the other comprises neurons that are tyrosine hydroxylase (TH)-IR. We have shown recently that TH-IR neurons are involved in esophageal-distention induced gastric relaxation. We used whole cell patch clamp techniques in rat brainstem slices combined with immunohistochemical and morphological reconstructions to characterize cNTS neurons. Postrecording reconstruction of cNTS neurons revealed two morphological neuronal subtypes; one group of cells (41 out of 131 neurons, i.e., 31%) had a multipolar soma, while the other group (87 out of 131 neurons, i.e., 66%) had a bipolar soma. Of the 43 cells in which we conducted a neurochemical examination, 15 displayed TH-IR (9 with bipolar morphology, 6 with multipolar morphology) while the remaining 28 neurons did not display TH-IR (18 with bipolar morphology, 10 with multipolar morphology). Even though the range of electrophysiological properties varied significantly, morphological or neurochemical distinctions did not reveal characteristics peculiar to the subgroups. Spontaneous excitatory postsynaptic currents (sEPSC) recorded in cNTS neurons had a frequency of 1.5 +/- 0.15 events s(-1) and an amplitude of 27 +/- 1.2 pA (Vh = -50 mV) and were abolished by pretreatment with 30 muM AP-5 and 10 muM CNQX, indicating the involvement of both NMDA and non-NMDA receptors. Some cNTS neurons also received a GABAergic input that was abolished by perfusion with 30-50 muM bicuculline. In conclusion, our data show that despite the heterogeneity of morphological and neurochemical membrane properties, the electrophysiological characteristics of cNTS neurons are not a distinguishing feature.

Visceral afferent and efferent connections in the brain.

Behavioral and physiological studies have revealed increasing evidence in thirst, hunger, energy and water metabolism for the importance of visceral input to the brain as well as central modulation of visceral events. Recent work in our laboratory has now revealed some new information about the central course of these afferent and efferent systems. From our work and others there is now good evidence that the bed of the hepatic-portal system contains sodium and osmoreceptors. Our electrophysiological and histochemical studies show that one branch overlaps the gustatory pathway. That is, involves the vagus nerve, nucleus tractus solitarius, parabrachial nucleus and ventro-basal thalamus (VBC). Another branch goes not to VBC but to the supra-optic nucleus. At the one level so far investigated clear evidence was obtained for convergence on single cells of visceral and gustatory inputs. It may well occur at other levels. A parallel and perhaps interacting efferent system more related to energy regulation has also been explored. The major parasympathetic output to the viscera are the axons of the brain stem dorsal-motor nucleus (DMV) forming the vagus nerves. We have shown that the paraventricular nucleus, which was known to project to DMV, is the only structure above the brain stem that has a direct input to DMV. However, since the nucleus of the solitary tract and reticular formation send fibers to the DMV the neural substrate exists for considerable indirect input. The significance of these results is that it provides a central neural substrate of the 2-way pathways linking brain and viscera. Thus, we now know more about neural control mechanisms involved in several motivational and metabolic systems. The close contiguity and even convergence of gustatory and visceral afferents may help to explain taste-aversion learning and alterations in the hedonics of taste under different nutritional states. The unique place of the paraventricular nucleus in relation to parasympathetic efferents will doubtless lead to new knowledge of the role of the brain in control of energy metabolism.

Vagal control of digestion: modulation by central neural and peripheral endocrine factors.

Vago-vagal reflex control circuits in the dorsal vagal complex of the brainstem provide overall coordination over digestive functions of the stomach, small intestine and pancreas. The neural components forming these reflex circuits are under significant descending neural control. By adjusting the excitability of the different components of the reflex, alterations in digestion control can be produced by the central nervous system. Additionally, the dorsal vagal complex is situated within a circumventricular region without an effective "blood-brain barrier". As a result, vago-vagal reflex circuitry is also exposed to humoral influences which profoundly alter digestive functions by acting directly on brainstem neurons. Behavioral and endocrine physiological observations suggest that this "humoral afferent pathway" may significantly alter the regulation of food intake.

Descending projections from the nucleus raphe obscurus to pudendal motoneurons in the male rat.

Previous physiological and behavioral studies have shown that the nucleus raphe obscurus (nRO) modulates pelvic floor reflex function (Yamanouchi and Kakeyama [1992] Physiol. Behav. 51:575-579; Beattie et al. [1996] Soc. Neurosci. Abstr. 22:722.4; Holmes et al. [1997] Brain Res. 759:197-204). In the present study, small injections of fluorescent tracers were used to investigate direct descending projections from the rostral and caudal portions of the brainstem nRO to retrogradely labeled pudendal motoneurons (MN) in the male rat. The caudal nRO projects into the ventral and lateral funiculi of the spinal cord, with arborizations in the thoracic intermediolateral cell column; in laminae VII, IX, and X of the lumbosacral cord; and in the sacral parasympathetic nucleus (SPN). Many identified external anal sphincter and ischiocavernosus MNs appeared to be in direct apposition with fibers originating from the caudal nRO; and more than half of the bulbospongiosus MNs that were identified appeared to receive such descending input. In addition to the nRO spinal autonomic and pudendal motoneuronal targets, projections were observed to regions of the intermediate gray that contain interneurons organizing the pelvic floor reflexes and to MN pools that are involved in functionally related somatic activities. Finally, several neurons in the lumbar enlargement were labeled retrogradely with FluoroRuby after injections into the nRO and the immediately adjacent reticular formation. Thus, the nRO may be in a position to modulate the coordinated actions of autonomic preganglionic and functionally related skeletal MN activity involved in sexual and eliminative reflex functions.

Borrelia burgdorferi and other related spirochetes bind to galactocerebroside.

Spirochetes are agents of neurologic disease that may utilize specific neural cell surface molecules for adhesion. Borrelia burgdorferi, the etiologic agent of Lyme disease, bound to galactocerebroside (GalCer) in numbers that were two- to threefold greater than to ceramide and glucocerebroside, and four- to fivefold greater than to sphingosine, psychosine, sulfatide, cholesterol, and three membrane phospholipids. The adherence was greater to GalCer and ceramide with a higher content of alpha-hydroxyl fatty acids. Treponema phagedenis Reiter and Borrelia hermsii also bound to GalCer. The binding of B burgdorferi to GalCer was inhibited in a concentration-dependent manner by rabbit polyclonal and murine monoclonal antibodies to this glycosphingolipid component of myelin. The monoclonal antibody to GalCer also inhibited adhesion of the organisms to Schwann cells. Neither free D or L monosaccharides nor the lectin peanut agglutinin inhibited binding. Since B burgdorferi and other spirochetes cause neurologic disease, these results suggest a role for GalCer as a binding site in both the central and peripheral nervous systems.

Selective gastric projections of nitric oxide synthase-containing vagal brainstem neurons.

Nitric oxide has been proposed to act as an intercellular messenger in central brainstem circuits controlling gastrointestinal motility. In particular, a subpopulation of preganglionic vagal neurons of the dorsal motor nucleus of the vagus have been shown to be reduced nicotinamide adenine dinucleotide phosphate(NADPH)-diaphorase positive; NADPH-diaphorase positive preganglionic fibers are also known to make contact with enteric neurons in the stomach. No studies, however, have correlated the neurochemical phenotype of preganglionic vagal neurons to their stomach target. The purpose of this study was to identify the subpopulation of nitric oxide synthase positive vagal neurons projecting to the stomach. Fluorescent retrograde tracers were injected in the fundus, corpus or antrum (Rhodamine beads) or painted on the anterior gastric branch of the vagus (DiI); five to 15 days later the brainstem was processed for nitric oxide synthase immunoreactivity. Of the 532 DiI-labeled neurons from the vagal anterior gastric branch, 25 (4.7%, n=5 rats) were co-localized with nitric oxide synthase immunoreactivity. Of the neurons labeled following injection of rhodamine beads in the antrum (N=231 neurons, n=5 rats) or corpus (N=166 neurons, n=4 rats) only three neurons showed nitric oxide synthase immunoreactivity (two in antrum and one in corpus, respectively). Conversely, 26 of 222 neurons (12%, n=7 rats) labeled following injection of rhodamine in the fundus showed nitric oxide synthase immunoreactivity. These results provide evidence for a discrete phenotypic subpopulation of vagal motoneurons that project to the gastric fundus, and suggest that these neurons may be the ones involved in the receptive relaxation reflex.

Clinical and behavioral characteristics in FG syndrome.

FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974. Based on over 50 reported cases, FG syndrome is associated with agenesis of the corpus callosum, minor facial anomalies (high, broad forehead with frontal cowlick, ocular hypertelorism, down-slanted palpebral fissures, and small cupped auricles), relative macrocephaly, broad thumbs and halluces, and prominent fetal fingertip pads. Affected individuals manifest neonatal hypotonia and severe constipation, which usually resolves during mid-childhood. The hypotonia with joint hyperlaxity evolves into spasticity with joint contractures in later life. Affability, hyperactivity, and excessive talkativeness are noted frequently in patients with FG syndrome. Recently, we described three additional families (six additional patients) with FG syndrome who support the localization of a gene for the FG syndrome in chromosome region Xq12-q21 [Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rodgers C, Corning K, Schwartz CE. 1998. Am J Med Genet 80:145-156.]. Using these same families and one additional sporadic case of FG syndrome, we compared behavioral and personality characteristics of 6 FG boys with other boys with syndromic and nonsyndromic mental retardation: eight with Down syndrome, seven with Prader-Willi syndrome, eight with nonspecific mental retardation, and 13 with Williams syndrome. Using the Vineland Adaptive Behavior Scales, the Reiss Personality Profiles, and the Achenbach Child Behavior Checklist, parents were asked to characterize the behavior and personality of their boys from ages 4 to 10 years. When compared with Williams syndrome, the FG boys had fewer internalizing behaviors and were significantly less anxious and withdrawn but had similar socially oriented, attention-seeking behaviors. On the Reiss Profile, FG boys were also quite similar to Williams syndrome boys. On the Vineland Scales, FG boys demonstrated significant relative strengths in their socialization skills, consistent with their personality, tending to confirm previous descriptions of their personalities.

Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion?

J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-+ ++D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magnesis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A).

Brachmann-de Lange syndrome: diagnostic difficulties posed by the mild phenotype.

We describe 4 patients with facial changes of Brachmann-de Lange syndrome but without limb defects. Mental retardation ranged from moderate to severe and the degree of prenatal and postnatal growth deficiency was variable. These patients exemplify the diagnostic difficulties and counseling dilemmas posed by the mild Branchmann-de Lange phenotype. The relationship of the mild phenotype to the full syndrome will not be understood until the pathogenetic or causal factor(s) are delineated.

Fragile X syndrome: growth, development, and intellectual function.

We collected data on growth, psychomotor development, speech and language development, and intellectual function on a cohort of 100 males with the fragile X chromosome and 95 carrier females. The data include information on prenatal growth (33 males), growth during the preadult years (32 males), psychomotor development during the first 2 years (25 males), speech and language development (15 males and 5 females), and intellectual function (93 males, 33 females, and 10 obligate carriers who were cytogenetically normal). Birth measurements appeared normal when plotted on the Usher/McLean curves of newborn infants (mean head circumference - OFC - at 40th centile, length at 60th centile and weight at 55th centile). Following birth, OFC rose above the 50th percentile and continued above average throughout the preadult years, whereas average length was above average for the first 5 years only and weight did not deviate from the normal mean. Psychomotor development lagged behind the norm from birth with affected males requiring nearly twice as long as expected to sit alone, walk unassisted, and say first words clearly. All males and females studied had significant language delay; all except one male had abnormalities of articulation. All on whom a clear voice sample was obtained had low voice pitch, and 80% had a hoarse or harsh quality of voice. Five males had word repetitions or perseverative speech during the preadult years. The mean IQ of the 93 males studied was 33 and regression analysis demonstrated a decrease in intellectual performance with age. Four fifths of the female carriers who expressed the fra(X) had intellectual performance in the mentally retarded range and showed similar decrease in performance with age. Obligate female carriers who did not express the fra(X) site had normal IQs (IQ 102 +/- 13.3).

Albright hereditary osteodystrophy and del(2) (q37.3) in four unrelated individuals.

Albright hereditary osteodystrophy (AHO) is a condition with characteristic physical findings (short stature, obesity, round face, brachydactyly) but variable biochemical changes (pseudohypoparathyroidism, pseudopseudohypoparathyroidism). Most patients with AHO have decreased activity of the guanine nucleotide-binding protein (GS protein) that stimulates adenylyl cyclase. The gene encoding the alpha subunit of the GS protein (GNAS1) has been mapped to the long arm of chromosome 20. We describe 4 unrelated individuals with apparent AHO, associated with small terminal deletions of chromosome 2. All 4 patients had normal serum calcium levels consistent with pseudopseudohypoparathyroidism. Del(2) (q37) is the first consistent karyotypic abnormality that has been documented in AHO [Phelan et al., 1993: Am J Hum Genet 53:484]. The finding of the same small terminal deletion in 4 unrelated individuals with a similar phenotype suggests that a gene locus in the 2q37 region is important in the pathogenesis of Albright syndrome. The association of Albright syndrome and the GNAS1 locus on chromosome 20 is well documented. The observation of a second potential disease locus on chromosome 2 may help explain the heterogeneity observed in this disorder.