De novo unbalanced translocations have a complex history/aetiology

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing

Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy.

Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2alpha kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K(+) channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg. kg(-1). day(-1), insulin was discontinued. Blood glucose did not deteriorate, and HbA(1c) was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment

Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy.

Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2alpha kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K(+) channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg. kg(-1). day(-1), insulin was discontinued. Blood glucose did not deteriorate, and HbA(1c) was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment

Bilateral radial agenesis with absent thumbs, complex heart defect, short stature, and facial dysmorphism in a patient with pure distal microduplication of 5q35.2-5q35.3

<p>Abstract</p> <p>Background</p> <p>A partial duplication of the distal long arm of chromosome 5 (5q35-- > qter) is known to be associated with a distinct phenotype referred to as Hunter-McAlpine syndrome. Clinical spectrum of this disorder mainly consists of mental retardation, microcephaly, short stature, skeletal anomalies, and craniofacial dysmorphism featuring flat facies, micrognathia, large, low-set dysplastic ears, hypertelorism, almond-shaped, down-slanted palpebral fissures, epicanthal folds, small nose, long philtrum, small mouth, and thin upper lip. Less frequent remarkable findings include craniosynostosis, heart defect, hypoplastic phalanges, preaxial polydactyly, hypospadias, cryptorchidism, and inguinal hernia. In most patients with a partial duplication of 5q the aberration occurred due to an inherited unbalanced translocation, therefore the phenotype was not reflective of pure trisomy 5q.</p> <p>Case presentation</p> <p>We report on a 9.5-year-old boy with some feature of Hunter-McAlpine syndrome including short stature, complex heart defect (dextrocardia, dextroversion, PFO), bilateral cryptorchidism, hypothyroidism, and craniofacial dysmorphism. Additionally, bilateral radial agenesis with complete absence of Ist digital rays, ulnar hypoplasia with bowing, choroidal and retinal coloboma, abnormal biliary vesicle were identified, which have never been noted in 5q trisomy patients. Karyotype analysis, sequencing and MLPA for <it>TBX5</it> and <it>SALL4</it> genes were unremarkable. Array comparative genomic hybridization detected a duplication on 5q35.2-5q35.3, resulting from a <it>de novo</it> chromosomal rearrangement. Our proband carried the smallest of all previously reported pure distal 5q trisomies encompassing terminal 5.4-5.6 Mb and presented with the most severe limb malformation attributed to the increased number of distal 5q copies.</p> <p>Conclusions</p> <p>We postulate that a terminal distal trisomy of 5q35.2-5q35.3, which maps 1.1 Mb telomeric to the <it>MSX2</it> gene is causative for both radial agenesis and complex heart defect in our proband. A potential candidate gene causative for limb malformation in our proband could be <it>FGFR4</it>, which maps relatively in the closest position to the chromosomal breakage site (about 1.3 Mb) from all known 5q duplications. Since the limb malformation as well as the underlying genetic defect are distinct from other 5q trisomy patient we propose that a position effect resulting in altered long-range regulation of the <it>FGFR4</it> (alternatively <it>MSX2</it>) may be responsible for the limb malformation in our proband.</p