You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.


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, )

Neurogenetic evidence in the courtroom: a randomised controlled trial with German judges

23 Sep, 15 | by hqqu

Prominent court decisions and research suggest that presentation of neuro-genetic evidence may reduce the sentence of convicted psychopaths. In a mock case, we presented German judges with a hypothetical case vignette of aggravated battery and randomly assigned them to expert testimonies that either involved a neuro-genetic explanation of the offender’s psychopathy or not.

We found that neuro-genetic evidence significantly reduced judges’ estimation of legal responsibility. Moreover, neuro-genetic arguments presented by the prosecution significantly increased the number of judges (23% compared to ~6%) ordering an involuntary commitment in a forensic-psychiatric hospital. Such an involuntary commitment may last much longer than a prison sentence in the German legal system. Our data thus demonstrates the socially contingent nature of legal responses to neuro-genetic evidence. (By Dr. Johannes Fuss,


From left to right: Prof. Peer Briken and Dr. Johannes Fuss

Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay

16 Sep, 15 | by hqqu

A homozygous mutation in the FTO gene encoding a 2-oxoglutarate dependent oxygenase was previously identified as the cause of a syndrome characterized by growth retardation and multiple malformations. No other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations. We investigated a 21-month-old girl who presented with growth retardation and global developmental delay. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents and identified a novel FTO homozygous missense substitution p.(Ser319Phe) in the patient. Biochemical studies reveal that this substitution reduces the catalytic activity of the FTO protein. Our findings reinforces the hypothesis that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome and further support the proposal that FTO plays an important role in early development of the human central nervous system. (By Dr. Hussein Daoud, )

Melanoma Genetics

3 Sep, 15 | by hqqu

Although the majority of melanomas develop due to cell damage caused by ultraviolet (UV) radiation exposure, susceptibility to melanoma is also influenced by genetics. For some families, inheritance of particular melanoma ‘risk’ genes can predispose to developing melanoma. These are grouped into ‘high’, ‘medium’ and ‘low’ penetrance genes, where penetrance reflects the likelihood of melanoma occurring over time in a person who carries the genetic mutation or polymorphism. Although no single mutation/variant guarantees disease development, the main impact is elevation of baseline melanoma risk, and it is likely that multiple low penetrance genes along with genetic and environmental modifiers combine to elicit a unique level of personal melanoma risk. In addition to cutaneous melanoma, some ‘melanoma’ predisposition genes have been linked to risk of other cancers. (By Dr. Jazlyn Read, )

Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with Multiple Lentigines

2 Sep, 15 | by hqqu

Noonan syndrome with multiple lentigines, (NSML) formerly known as LEOPARD syndrome, has overlapping features with other RASopathies. Except for neurofibromatosis type 1, other disorders that result from dysregulated RAS/MAPK pathway are not known to be associated with neurogenic tumors. We identified four patients from three families with NSML, progressive neuropathy, enlarged nerves, massive burden of paraspinal neurofibromas and a mutation in the PTP catalytic domain of the PTPN11 gene (p.Thr468Met and p.Thr279Cys). Analysis of hypertrophic nerve did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes. Neurogenic tumors and hypertrophic neuropathy may be under-recognized manifestations of NSML that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation. (By Drs. Dusica Babovic-Vuksanovic and Erin Conboy, )

Blog Figure 3

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

21 Aug, 15 | by hqqu

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and distinctive brain MRI findings. Diagnosis and treatment of JS is challenging due to >28 associated genes and substantial clinical variability. This study provides a relatively unbiased view of the phenotypic range, genetic basis, and gene-phenotype associations in >500 individuals with JS. This information is crucial for diagnostic and carrier testing, medical monitoring for progressive complications, and interpretation of variants identified through genome-wide sequencing results. Understanding the genetic basis of JS is facilitating the development of gene-specific treatments. (By Dr. Dan Doherty, )

Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure

21 Aug, 15 | by hqqu

Primary gonadal failure is characterized by a lack of spontaneous pubertal development, primary amenorrhea or early menopause in females, and underdeveloped testis and azoospermia in males. Its genetic causes remain mostly unknown.

Variants of the minichromosome maintenance complex component 8 gene (MCM8) are significantly associated with early menopause. Mice lacking MCM8 are sterile. We sought to elucidate the genetic etiology of gonadal failure in two consanguineous families: family 1’s index case presented with primary amenorrhea and her brother had azoospermia; family 2’s five affected females had primary amenorrhea.

Using whole-exome sequencing, we identified two novel homozygous mutations in MCM8—splice (c.1954-1G>A) and frameshift (c.1469-1470insTA)—that segregated with the disease and were absent in 100 ethnically matched controls. The splice mutation (family 1) led to three different aberrant transcripts and a significant decrease in total MCM8 message. The frameshift mutation (family 2) predicted a premature stop codon. DNA-repair capabilities showed significantly increased chromosomal breakage.

Our findings indicate that MCM8 is crucial for gonadal development and maintenance and suggest its relevance in the larger context of reproductive lifespan in humans. (By Dr. Yardena Tenenbaum-Rakover, )

Figure 1

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

21 Aug, 15 | by hqqu

In March 2014 the International Gastric Cancer Linkage Consortium, a group of worldwide experts in the field of Hereditary Diffuse Gastric Cancer, held a consensus meeting in the Radboudumc in Nijmegen, The Netherlands. During this three-day meeting, the current evidence and world-wide experience for managing individuals with a family history of diffuse type gastric cancer was discussed. New criteria for CDH1 mutation testing, as well as updated endoscopy screening and surveillance protocols are described in the revised guideline. Additionally, the treatment of carriers of germline CDH1 mutations are extensively discussed including prophylactic surgery as well as nutritional and psychological needs. (By Dr. Ingrid Vogelaar, )


The IGCLC group

A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life

21 Aug, 15 | by hqqu

Hypertrophic Cardiomyopathy (HCM) is one of the most common inherited cardiac disorders with a prevalence of 1:500. It is characterized by unexplained left ventricular hypertrophy (from 13 mm to more than 35 mm) that develops in the absence of an underlying systemic condition or other cardiac disease. The most serious manifestations of HCM are sudden death and progressive heart failure. The majority of causal mutations are identified in genes encoding proteins of the sarcomere.

In this study we report the identification of a founder mutation in MYBPC3 gene in 20% of our Italian HCM patients. We found that the probability to develop the disease in mutation carriers is higher between 30 and 40 years of age, with a major risk if they are men. Probands carrying the founder mutation showed a higher prevalence of non-sustained ventricular tachycardia and ICD implantation with a significantly reduced survival after the fourth decade of life, when compared with patients negative for MYBPC3 mutations. (By Dr. Alessandra Rampazzo, )

JMG blog homepage

JMG Contact

Research developments and evidence-based medical genetics. Visit site

Creative Comms logo

Latest from Journal of Medical Genetics

Latest from Journal of Medical Genetics