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Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family

14 Nov, 15 | by hqqu

We investigated a large consanguineous family from Pakistan comprising multiple affected individuals with intellectual disability and epilepsy. Using a combination of next-generation and classical sequencing methods, we identified a bi-allelic missense mutation p.R53Q in the LMAN2L gene only in the patients and not in the unaffected family members. LMAN2L encodes for a protein playing a central role in quality control processes of protein glycosylation. This is the first report linking LMAN2L to the phenotype of severe intellectual disability and seizures. (By Rafiullah Rafiullah & Dr. Simone Berkel, )

Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith–Wiedemann syndrome

7 Nov, 15 | by hqqu

We report the largest group of patients to date with hyperinsulinism (HI) and Beckwith-Wiedemann syndrome (BWS). Our study shows that BWS children with severe, persistent HI have a particular form of BWS caused by two copies of part of chromosome 11 inherited from the father (paternal uniparental isodisomy for chromosome 11; pUPD11p). Three-fourths of these children required intensive treatment for their HI, including pancreatic surgery in half of the cases. Pancreas samples from these children showed large areas of overgrowth of insulin producing cells. In most cases, there was no other identified genetic cause of HI, suggesting that pUPD11p alone can cause severe HI. Recognizing BWS in children with HI is important because children with BWS require long-term monitoring for embryonal tumors. (By Dr. Jennifer Kalish, )

UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN

7 Nov, 15 | by hqqu

NALCN is a voltage-independent cation channel that controls neuronal excitability. NALCN is known to interact with two other proteins, UNC79 and UNC80, which together form an active channel complex in hippocampal neurons. Thus, regulation of the UNC79-UNC80-NALCN channel complex is extremely important for controlling neuronal excitability. Our study presents a novel syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, caused by a nonsense UNC80 mutation. This mutation likely generates a dramatically truncated non-functional UNC80 protein leading to malfunction of the UNC79-UNC80-NALCN active complex, in line with the UNC80 mutation phenotype being similar to that stemming from NALCN null-function mutations. (By Yonatan Perez and Prof. Ohad Birk, )


From left to right: Yonatan Perez and Prof. Ohad Birk

Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin–Siris syndrome

6 Nov, 15 | by hqqu

The SOX11 gene encodes a transcription factor which regulates neuronal production during brain development. In mice, loss of SOX11 is associated with reduced brain size.  In this study, Hempel et al identify deletions or de novo mutations of SOX11 in children with neurodevelopmental delay, microcephaly and dysmorphism. Some of the reported individuals had features of Coffin-Siris syndrome such as fifth finger hypoplasia and sparse scalp hair. Experiments in cultured cells confirmed that the mutant SOX11 protein could not induce gene expression, supporting the disease causing nature of these mutations. Knockdown of Sox11 in xenopus resulted in microcephaly. Deletions and mutations of SOX11 can cause a neurodevelopmental disorder in man. (By Dr. Alisdair McNeill, )

Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families

3 Nov, 15 | by hqqu

The authors performed specific sequencing 17 known and putative breast cancer susceptibility genes in 660 women with familial breast cancer who did not carry a mutation the known susceptibility genes, BRCA1 or BRCA2. The authors then evaluated the putative cancer-related mutations and found in relevant family members to determine whether they were carried by affected family members. Only variants in the CDH1, CHEK2, PALB2 and TP53 genes showed evidence of a significantly increased risk of breast cancer, with some supportive evidence that mutations in ATM confer moderate risk. The authors found that panel testing for these breast cancer families provided additional relevant clinical information for <2% of families. (By Dr. Georgia Chenevix-Trench, )

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement

26 Oct, 15 | by hqqu

Dentists, geneticists and clinician-researchers studying tooth defects are often confronted by patients with genetic disorders that have striking dental defects such as the absence of some or several teeth, loss or defects in tooth enamel, and cleft palate among others. These defects can have a significant impact on the health and quality of life of these patients. Diagnosing the genetic cause of such defects is quite challenging as hundreds of genes have been implicated in these disorders. Prasad and colleagues have developed a new diagnostic test that takes advantage of next-generation sequencing technologies to efficiently identify the genetic defect in patients with rare genetic disorders that affect the teeth and the oral cavity. This test will enable clinicians and researchers to determine the genetic cause of dental defects in a large number of patients, thus enabling better patient care and treatment. (By Dr. Megana Prasad, )

MKS1 regulates ciliary INPP5E levels in Joubert syndrome

22 Oct, 15 | by hqqu

Ciliopathies are disorders unified by shared pathophysiology and overlapping clinical phenotypes. MKS1 localizes to the base of the cilium, and MKS1 mutations are a major cause of the severe ciliopathy Meckel syndrome. We identified MKS1 mutations in nine families with the milder Joubert syndrome (JS), confirming a prior report linking MKS1 to JS. We demonstrate that JS-associated MKS1 mutations do not consistently alter cilium number or length, but they do reduce ciliary localization of ARL13B and consequently INPP5E. Given that INPP5E mutations also cause JS, we propose that INPP5E dysfunction is a central mechanism underlying JS, providing a pharmacologic target for future treatments. (By Gisela Slaats, )

High sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome

16 Oct, 15 | by hqqu

Somatic mosaicism arises following the occurrence of a mutation at some stage during the development of an embryo which is then propagated to only a select population of its cells. This phenomenon is being increasingly recognized as an important cause of isolated presentations of syndromes that are usually hereditary. The DICER1 syndrome is a rare pediatric tumor predisposition syndrome typically caused by inherited (germ-line) mutations in the DICER1 gene. We studied four children with multiple tumors known to be associated with the syndrome, but in whom germ-line DICER1 mutations were not detected by conventional mutation-detection techniques. We observed the same DICER1 mutation within a particular gene domain in multiple tumors from different anatomic sites in each patient. Using three sensitive targeted-capture technologies, including the novel HaloPlexHS (Agilent Technologies), we confirmed that the identified mutations are mosaic in origin in three of the four children. Our research confirms that mosaic DICER1 mutations are an important cause of DICER1 syndrome in severely affected patients. (By Dr. Leanne de Kock, )

Figure 1

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

30 Sep, 15 | by hqqu

The HACE1 gene encodes a ubiquitin ligase involved in regulating several small GTPases. It has previously been proposed to be a tumour suppressor, whose function is impaired in various forms of cancer. In this study, Hollstein et al. have identified biallelic null HACE1 mutations in eight individuals from two families with an autosomal recessive syndrome of intellectual disability, ataxia and spasticity. Neither the affected subjects nor unaffected mutation carriers displayed any cancer predisposition, suggesting that the heterozygous mutations previously observed in association with Wilms tumour are likely to have been coincidental findings. (By Dr. David Bonthron, )


Zollino et al KANSL1 haploinsufficiency syndrome

30 Sep, 15 | by hqqu

Among rare diseases, the KANSL1 haploinsufficiency syndrome is one of the most common conditions. It can be caused by a small deletion on chromosome 17, removing the KANSL1 gene and other genes, or by a mutation in KANSL1. By analysing a large cohort of patients, we found that the degree of cognitive impairment is very mild in most. More importantly, although chromosome deletions are more frequent than KANSL1 mutations, we observed that KANSL1 is the major gene for this condition. It palys a role in regulating the activity of many genes, by a DNA process defined as “histone acetylation”. Drugs with acetylating activity might eventually be used in targeted therapy of this condition. (By Prof. Marcella Zollino, )

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