Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5’ splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Cowden syndrome and the PTEN Hamartoma tumor syndrome: how to define rare genetic syndromes

Cowden syndrome (OMIM No. 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) (OMIM No. 153480) are autosomal dominant conditions described before the genetic testing era. The early reports of Cowden syndrome were by adult physicians and dermatologists who recognized a pattern of benign and malignant tumors affecting the breast and thyroid, accompanied by characteristic acral keratosis and trichilemmomas of the skin (1,2,3). BRRS was described by pediatricians and clinical geneticists, with the principle features being macrocephaly, delayed development, lipomata, hemangiomas, and vascular malformations, along with pigmented macules of the penis (4,5). Both conditions are caused by mutations in the PTEN gene (OMIM+601728) (6,7). There is no definite association between the type or position of mutation within the PTEN gene and the clinical presentation of the patient. Both conditions have been described in different members of the same family with the same mutations, and it is clear that meticulous examination reveals features of childhood-onset BRRS in adults presenting with the features of Cowden syndrome and vice versa. It is therefore generally accepted that they are one condition, with variable expression and age-related penetrance (8,9,10,11). Genetic heterogeneity has been reported with reports of Cowden-like patients(ie, those who do not fulfill criteria for PTEN hamartoma syndrome [PHTS]) with mutations in SDHB, SDHD, AKT, and PIK3CA, as well as hypermethylation of the promoter of the KLLN gene (12,13,14,15)

Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers

BACKGROUND: The most commonly reported phenotypes described in patients with PTEN mutations are Bannayan-Riley-Ruvalcaba syndrome (BRRS), with childhood onset, macrocephaly, lipomas and developmental delay, and Cowden Syndrome (CS), an adult-onset condition recognised by mucocutaneous signs, with a risk of cancers, in particular those of the thyroid and breast. It has been suggested that BRRS and CS are the same condition, but the literature continues to separate them and seek a genotype-phenotype correlation. OBJECTIVE: To study the clinical features of patients with known PTEN mutations and observe any genotype-phenotype correlation. METHODS: In total, 42 people (25 probands and 17 non-probands) from 26 families of all ages with PTEN mutations were recruited through the UK clinical genetics services. A full clinical history and examination were undertaken. RESULTS: We were unable to demonstrate a genotype-phenotype correlation. Furthermore, our findings in a 31-year-old woman with CS and an exon 1 deletion refutes previous reports that whole exon deletions are only found in patients with a BRRS phenotype. CONCLUSION: Careful phenotyping gives further support for the suggestion that BRRS and CS are actually one condition, presenting variably at different ages, as in other tumour-suppressor disorders such as neurofibromatosis type 1. This has important counselling implications, such as advice about cancer surveillance, for children diagnosed with BRRS

A clinical and molecular study of 26 females with Xp deletions with special emphasis on inherited deletions

We have undertaken a clinical study of 26 females with deletions of Xp including five mother–daughter pairs. Cytogenetic and molecular analyses have mapped the breakpoints of the deletions. We determined the parental origin of each abnormality and studied the X-inactivation patterns. We describe the clinical features and compare them with the amount of Xp material lost. We discuss the putative loci for features of Turner syndrome and describe how our series contributes further to their delineation. We conclude that (1) fertility can be retained even with the loss of two-thirds of Xp, thus, if there are genes on Xp for ovarian development, they must be at Xp11–Xp11.2; (2) in our sample of patients there is no evidence to support the existence of a single lymphogenic gene on Xp; (3) there is no evidence for a second stature locus in proximal Xp; (4) there is no evidence to support the existence of a single gene for naevi; (5) we suggest that the interval in Xp21.1–Xp11.4 between DXS997 and DXS1368 may contain a gene conferring a predisposition to hypothyroidism

Hereditary hyperferritinemia cataract syndrome: ocular, genetic, and biochemical findings

PURPOSE: To describe the cataract morphology and genetic and biochemical findings in a four-generation family with hereditary hyperferritinemia cataract syndrome (HHCS).METHODS: Family members of the proband with HHCS were investigated. DNA sequencing was carried out to identify the iron responsive element (IRE) of the L-ferritin gene in affected and non-affected family members. Molecular modeling allowed prediction of the structure of the mutant IRE in affected cases. Serum ferritin and transferrin saturation were determined using standard methods. All family members underwent slit lamp examination by an ophthalmologist to document presence of cataract or lens status. Cataract morphology was documented where present.RESULTS: This family with HHCS had the genetic heterozygous mutation G32C in the IRE of the L-ferritin mRNA. Lens opacities were detectable in young members of the family, and morphology of cataracts was consistent with previous reports. Biochemical testing demonstrated high serum ferritin levels in affected individuals.CONCLUSIONS: The morphology of cataracts in HHCS seems to be similar in all cases. In the heterozygous G32C mutation, the age at onset of cataracts is very early. Greater awareness of this condition among ophthalmologists will lead to effective family counseling of those affected, by genetic testing or simple biochemical tests. Serum ferritin levels can be effectively used to screen for this condition in suspected families