Mutations in WNT9B are associated with Mayer–Rokitansky–Küster–Hauser syndrome

Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS) is a well‐known malformation pattern of the Müllerian ducts (MDs) characterized by congenital absence of the uterus and vagina. To date, most cases remain unexplained at molecular level. As female Wnt9b‐/‐ mice show a MRKHS‐like phenotype, WNT9B has emerged as a promising candidate gene for this disease. We performed retrospective sequence analyses of WNT9B in 226 female patients with disorders of the MDs, including 109 patients with MRKHS, as well as in 135 controls. One nonsense mutation and five likely pathogenic missense mutations were detected in WNT9B. Five of these mutations were found in cases with MRKHS accounting for 4.6% of the patients with this phenotype. No pathogenic mutations were detected in the control group (p = 0.017). Interestingly, all of the MRKHS patients with a WNT9B mutation were classified as MRKHS type 1, representing 8.5% of the cases from this subgroup. In previous studies, two of the patients with a WNT9B mutation were found to carry either an additional deletion of LHX1 or a missense mutation in TBX6. We conclude that mutations in WNT9B were frequently associated with MRKHS in our cohort and some cases may be explained by a digenic disease model.     

Measuring gene–gene interaction using Kullback–Leibler divergence

Genome‐wide association studies (GWAS) are used to investigate genetic variants contributing to complex traits. Despite discovering many loci, a large proportion of “missing” heritability remains unexplained. Gene–gene interactions may help explain some of this gap. Traditionally, gene–gene interactions have been evaluated using parametric statistical methods such as linear and logistic regression, with multifactor dimensionality reduction (MDR) used to address sparseness of data in high dimensions. We propose a method for the analysis of gene–gene interactions across independent single‐nucleotide polymorphisms (SNPs) in two genes. Typical methods for this problem use statistics based on an asymptotic chi‐squared mixture distribution, which is not easy to use. Here, we propose a Kullback–Leibler‐type statistic, which follows an asymptotic, positive, normal distribution under the null hypothesis of no relationship between SNPs in the two genes, and normally distributed under the alternative hypothesis. The performance of the proposed method is evaluated by simulation studies, which show promising results. The method is also used to analyze real data and identifies gene–gene interactions among RAB3A, MADD, and PTPRN on type 2 diabetes (T2D) status.     

Prenatal diagnosis of Smith–Lemli–Opitz syndrome,type II

Smith–Lemli–Opitz syndrome, type II (SLOS-II) is a severe autosomal recessive disorder characterized by a distinctive face, unusual cleft palate, postaxial polydactyly, congenital heart defects, renal anomalies, and male pseudohermaphroditism. We present the first report of prenatal diagnosis of SLOS-II, as well as an additional report of prenatal detection of multiple anomalies, in which a positive diagnosis of SLOS II was made postanatally. In neither case was the pregnancy known prospectively to be at risk for SLOS-II. In the former case, targeted sonographic examination at 31 weeks of gestation showed intrauterine growth retardation, atrioventricular septal defect, mesomelic shortening of the arms, small kidneys, overlapping fingers, and female external genitalia; a 46,XY chromosome constitution had been ascertained previously. A provisional diagnosis of SLOS-II was made prenatally. In the latter case, targeted sonographic examination at 18 weeks of gestation showed severe oligohydramnios, atrioventricular septal defect, and Dandy–Walker malformation. The kidneys and bladder were not visualized. The chromosome constitution was 46,XX. The diagnosis of SLOS-II was made postnatally. In both cases, additional findings compatible with SLOS-II were noted postnatally. Prenatal detection of congenital heart defects and renal abnormalities, in combination with certain additional findings (most notably, female external genitalia in the presence of a 46,XY karyotype, polydactyly, disproportionately short limbs, or intrauterine growth retardation) and a normal karyotype, suggests the diagnosis of SLOS-II, and warrants further investigation. © 1994 Wiley-Liss, Inc.     

Spontaneously regressing brain lesions in Smith–Lemli–Opitz syndrome

Smith–Lemli–Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals’ clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.

     

Genotype–phenotype specificity in Menke–Hennekam syndrome caused by missense variants in exon 30 or 31 of CREBBP

CREBBP loss‐of function variants cause Rubinstein–Taybi syndrome (RTS). There have been two separate reports of patients with missense variants in exon 30 or 31 of CREBBP in individuals lacking the characteristic facial and limb dysmorphism associated with RTS. Frequent features in this condition include variable intellectual disability, short stature, autistic behavior, microcephaly, feeding problems, epilepsy, recurrent upper airway infections, and mild hearing impairment. We report three further patients with de novo exon 31 CREBBP missense variants. The first individual has a c.5357G>A p. (Arg1786His) variant affecting the same codon as one of the previously described patients. Both these patients could be recognized by clinicians as mild RTS. Our second patient has a c.5602C>T p.(Arg1868Trp) variant that has been described in five other individuals who all share a strikingly similar phenotype. The third individual has a novel c.5354G>A p.(Cys1785Try) variant. Our reports expand the clinical spectrum to include ventriculomegaly, absent corpus callosum, staphyloma, cochlear malformations, and exomphalos. These additional cases also help to establish genotype–phenotype correlations in this disorder. After the first and last authors of the previous two reports, we propose to call this disorder “Menke–Hennekam syndrome” to establish it as a clinical entity distinct from RTS and to provide a satisfactory name for adoption by parents and professionals, thus facilitating appropriate clinical management and research.     

Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL–PEG–PCL hydrogel. Part 2: Sol–gel–sol transition and drug delivery behavior

In this work, a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCEC) hydrogel was studied. The prepared PCEC hydrogel undergoes temperature-dependent sol–gel–sol transition, which is a flowing sol at ambient temperature and turns into a non-flowing gel at around physiological body temperature. Furthermore, the sol–gel phase transition mechanism was investigated using ¹³C-nuclear magnetic resonance imaging and a laser diffraction particle size analyzer. The in vitro release behaviors of several model drugs, including a hydrophilic small-molecule drug, a hydrophobic small-molecule drug and a macromolecular protein drug, from PCEC hydrogel were also investigated in detail. The results showed that the model drugs could be released from the PCEC hydrogel system over a sustained period. In addition, an anaesthesia assay was conducted using the tail flick latency (TFL) test to evaluate the in vivo controlled drug delivery effect of the PCEC hydrogel system. In the TFL assay, a lidocaine-loaded PCEC hydrogel produced significantly longer-lasting local anaesthetic effects compared with lidocaine aqueous solution at the same dose. Therefore, PCEC hydrogel is promising for use as an injectable local drug delivery system.