Prenatal Diagnosis of Agenesis of the Corpus Callosum and Cerebellar Vermian Hypoplasia Associated with a Microdeletion on Chromosome 1p32

We present the prenatal detection of a 1p32.1p31.3 microdeletion (3.46 Mb) by array comparative genomic hybridization (CGH) associated with fetal agenesis of the corpus callosum (ACC) and cerebellar vermian hypoplasia. Analysis of cultured amniocytes showed a normal karyotype. Our observations strengthen the association between this locus and central nervous system development. In addition, the fetus reported herein underscores the importance of array CGH analysis when ACC is detected prenatally, especially when there are additional central nervous system anomalies, to search for submicroscopic imbalances which can facilitate further management and parental counselling. Moreover, the presence of urinary tract anomalies should alert the clinician to the possibility of a 1p interstitial deletion, although the absence of such does not exclude it. Further reports will help to provide more information on the long-term outcomes of individuals with such microdeletion as there are only limited data.published_or_final_versio

Homozygous Missense Mutation in ABR Causes Cerebellar Hypoplasia with Early Lethality - A New Condition Identified by Exome Sequencing?

Poster PresentationWe performed whole exome sequencing (WES) in a consanguineous Pakistani family with a recurrent pattern of cerebellar hyposplasia, intra-uterine growth restriction, and various CNS/non-CNS malformations, resulting in early lethality (1 perinatal death and 1 intrauterine death). Karyotype (in the first pregnancy) and oligonucleotide array (in the 2nd affected pregnancy) were normal. Parents declined post-mortem examination. By WES, a novel homozygous missense mutation was identified in the ABR gene (ABR: NM_021962.4:c.G2455T: p.A819S) in both affected pregnancies. Both parents were identified to be heterozygous of the same mutation while the healthy child did not carry any mutation. The mutation is located in a highly conserved region and is predicted to be highly damaging by all the commonly used in silico mutation prediction tools. The protein encoded by ABR gene contains a GTPase-activating protein domain, a domain found in members of the Rho family of GTP-binding proteins. Previous reports showed that OPHN1, mutations in which cause X-linked mental retardation with cerebellar hypoplasia (OMIM300486), also encodes for a regulator of GTPase-activating protein. Both OPHN1 and ABR are highly expressed in the human brain especially in the cerebellum, and both contain a GTPase-activating domain. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Other studies have demonstrated a regulatory role of Rho GTPase in differentiation of cerebellar neurons, and that ethanolassociated impairment of Rho GTPase might contribute to brain defects in fetal alcohol syndrome. Further functional studies, including zebrafish morpholino studies, are currently ongoing. WES can be helpful in individual families with undiagnosed lethal MCA syndromes to identify potentially responsible autosomal recessive mutations and may lead to a better understanding of the role of various developmental pathways in human embryogenesis.published_or_final_versio

Lifestyle modifications in the development of diabetes mellitus and metabolic syndrome in Chinese women who had gestational diabetes mellitus: a randomized interventional trial

Objectives: To study whether lifestyle intervention can reduce the development of type II diabetes mellitus (DM) and metabolic syndrome (MS) among Chinese women who had gestational diabetes mellitus (GDM). Methods: A prospective randomized controlled interventional trial of 450 women who had GDM and impaired glucose tolerance (IGT) postpartum. Advice on diet and exercise was given to the intervention group and reinforced in each follow-up visit. Women in both arms were followed for 36 months. Blood pressure and anthropometry were measured at each visit and blood tests were repeated. Results:Fewer women in the intervention group developed DM (15 versus 19 %) but this was not statistically significant, and there was a lower incidence of DM among women over 40 years old. No difference was found in fasting glucose, insulin and homeostasis model assessment (HOMA) index. Both systolic and diastolic blood pressures, and triglyceride level, were lower but the significance was inconsistent among visits. BMI and percentage body fat were also significantly lower in the later visits. There was no difference in waist-hip ratio and basal metabolic rate. Conclusions: Our results demonstrate a trend towards lower incidence of type II DM within 3 years postpartum in GDM women given lifestyle advice, which also potentially offers protection against development of MS, in terms of lower blood pressure and triglyceride level. Women over 40 years old are more likely to benefit. Future studies should address ways to maximize compliance to lifestyle intervention as its potential benefits can be undermined by challenges of motherhood

Homozygous missense mutation in ABR causes cerebellar hypoplasia with early lethality: a new condition identified by exome sequencing?

pp. 1685-1740 of this journal issue entitled: 35th Annual David W Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2014 Annual MeetingLink_to_subscribed_fulltex