Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved. In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome. In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance. The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain. Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity. Our results emphasize the importance of phosphoinositide signalling in early brain development.

Objective To determine in vivo whether monochorionic pregnancies complicated by twin-to-twin transfusion syndrome are associated with absence of haemodynamically-compensatory arterioarterial anastomoses.Design Forty monochorionic pregnancies were prospectively recruited for an ultrasonographic survey of the chorionic plate using colour Doppler energy. Arterio-arterial anastomoses were identified by their characteristic bidirectional interference pattern on spectral Doppler. Angioarchitecture was confirmed by postnatal injection study.Setting Fetal medicine tertiary referral centre in London. Main Outcome MeasuresPresence of arterio-arterial anastomoses, development of twin-to-twin transfusion syndrome, survival.Results Arterio-arterial anastomoses were detected by colour Doppler energy in 2 1 pregnancies (53%), and there were no false positives. An arterio-arterial anastomosis was more commonly found in unaffected (n = 28) compared to pregnancies affected by twin-to-twin transfusion syndrome (n = 12), both by colour Doppler energy [20/28 (71%) vs 1/12 (8%); A = 63%, 95% CI 400/1A6%;,] and by postnatal injection study [25/28 (89?4) vs 3/12 (25%); A = 64%, 95% CI 37%-91%]. In pregnancies in which no arterio-arterial anastomoses were detected, a diagnosis of twin-to-twin transfusion syndrome was made in 58%, and the perinatal loss rate was 40%, compared with one case of twin-to-twin transfusion syndrome (5%) (P C 0.001) and a loss rate of 12% (P = 0.005) in pregnancies in which an arterio-arterial anastomosis was detected.Conclusion Twin-to-twin transfusion syndrome is associated with an absence of functional arterioarterial anastomoses in vivo in monochorionic twin pregnancies. This contributes to our understanding of the pathophysiology of twin-to-twin transfusion syndrome and confirms ex vivo studies demonstrating that twin-to-twin transfusion syndrome is associated with a paucity of superficial anastomoses. Prospective studies are indicated to determine the utility of colour Doppler energy for arterio-arterial anastomoses in predicting risk in monochorionic pregnancies.

The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24–28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r2=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.

In this report we describe two cases of fetal midline intracranial cyst presenting with ventriculomegaly at routine detailed second‐trimester scan. In the first case, additional findings included a banana‐shaped hypoplastic cerebellum and macrocephaly; autopsy after termination of the pregnancy revealed a glioependymal cyst. In the second case, subsequent follow‐up examination revealed a progressive increase in cyst size and worsening of ventriculomegaly; termination of pregnancy was performed at 24 weeks and autopsy confirmed an arachnoid cyst. These cases document interhemispheric cyst as a cause for early ventriculomegaly in utero.