Background
Gerstmann Sträussler Scheinker (GSS) is an inherited, invariably fatal prion disease. Like other human prion diseases, GSS is caused by missense mutations in the prion protein (PrP) gene (
...PRNP
), and by the formation and overtime accumulation of the misfolded, pathogenic scrapie PrP (PrPSc). The first mutation identified in the
PRNP
gene, and the one blamed as the main cause of the disease, is c.C305T:p.P102L.
Methods and results
The Sanger sequencing method was performed on the
PRNP
gene for the detection of c.C305T:p.P102L mutations in a cohort of 10 subjects; moreover, a study was carried out, using Next Generation Sequencing (NGS), by sequencing a group of genes related to amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), movement disorders and dementia which show a phenotypic profile similar to that of GSS. The results obtained from the study using NGS indicate the potential role of other genetic variants which could contribute to the various GSS phenotypes.
Conclusions
In conclusion, we highlight the large clinical variability in subjects presenting with GSS and p.P102L, as well as the hypothesis that the mutation in PrP codon 102 alone is not sufficient to trigger the cardinal clinical signs of the disease; furthermore, we do not exclude the possibility that further genetic variants play a decisive role in the aspects of the various phenotypes with which GSS manifests itself.
Coffin-Lowry syndrome is a semi-dominant condition characterized by severe psychomotor retardation with facial, hand and skeletal malformations resulting from mutations in RSK2 gene, encoding for a ...serine/threonine kinase. More than 100 different mutations have been identified to date; however, about 50% of clinically diagnosed patients apparently do not have mutations. In order to exclude that these patients have RSK2 mutations missed by standard mutation detection techniques, a rapid and sensitive assay allowing evaluation of RSK2 activity was needed.
RSK2 capacity to phosphorylate a synthetic CREB-peptide in basal and PMA-stimulated conditions was evaluated in lymphoblasts from 3 patients with RSK2 mutations and normal controls.
Patients RSK2 activity is normal in nonstimulated conditions but fails to grow following stimulation. The evaluation of the stimulated/non-stimulated activity ratio demonstrated a statistically significant impairment in patients.
We have set up an assay which allows the identification of even partial alterations of RSK2 activity and seems to give good results also in females with a balanced X-chromosome inactivation and thus with a presumably normal enzymatic activity in about 50% of cells. Moreover, our data seem to confirm previous reports of a potential direct correlation between the level of RSK2 activity and the severity of cognitive impairment.
In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for ...unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.
The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental ...delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.
We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease ...risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32–0.38, p < 10−126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10−4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24–0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09–0.22, p < 10−92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of “genetic anticipation” in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05–0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.
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Many rare genetic variants are variably expressive, conferring risk for a range of clinical features with incomplete penetrance. We implicate assortative mating as a risk factor for disease in families carrying these variants by increasing genetic disease liability over generations, leading to the “genetic anticipation” observed in these families.
A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset ...Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ɛ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans.
To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects.
Genotyping for rs1801133 was performed with PCR-RFLP techniques.
In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01-1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03-1.73) resulted in increased LOAD risk. Similarly, in APOEɛ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25-6.32). Very interestingly, also in non-APOEɛ4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03-1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing.
The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOEɛ4 or in non-APOEɛ4 carriers.
Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and ...drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the
ACTL6B
gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted
ACTL6B
sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with
ACTL6B
gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene–disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of
ACTL6B
gene mutation in a syndromic form of DEE.
STUDY QUESTION
Are DNMT3B promoter polymorphisms among maternal risk factors for the birth of a child with Down syndrome (DS)?
SUMMARY ANSWER
Present results suggest that combinations of functional ...DNMT3B promoter polymorphisms might modulate maternal risk of birth of a child with DS.
WHAT IS KNOWN ALREADY
The DNMT3B gene codes for DNA methyltransferase 3b (DNMT3b), a protein required for genome-wide de novo methylation, for the establishment of DNA methylation patterns during development and for regulating the histone code and DNA methylation at centromeric regions. Two common functional DNMT3B promoter polymorphisms, namely –149 C > T (rs2424913) and −579 G > T (rs1569686), have been extensively investigated in cancer genetic association studies but less is known about their role in non-cancer diseases. Early in 1999, it was supposed that impaired DNA methylation of pericentromeric regions might represent a maternal risk factor for having a baby with DS.
STUDY DESIGN, SIZE AND DURATION
We aimed to investigate DNMT3B –149 C > T and −579 G > T polymorphisms as maternal risk factors for the birth of a child with DS. The study was performed on DNA samples from 172 mothers of DS individuals (135 aged <35 years when they conceived) and 157 age-matched mothers of unaffected individuals.
PARTICIPANTS/MATERIALS, SETTING AND METHODS
Genotyping was performed by means of the PCR-RFLP technique.
MAIN RESULTS AND THE ROLE OF CHANCE
The DNMT3B −579T allele odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.48–0.94, P = 0.02, the DNMT3B −579 GT genotype (OR = 0.55; 95% CI = 0.35–0.87 , P = 0.01) and the combined DNMT3B −579 GT + TT genotype (OR = 0.55; 95% CI = 0.36–0.86 , P = 0.008) were associated with reduced risk of birth of a child with DS. A joint effect of the two polymorphisms was observed and the combined −579 GT/–149 CC genotype resulted in decreased DS risk (OR = 0.22; 95% CI = 0.08–0.64, P = 0.003). The effect remained statistically significant after Bonferroni's correction for multiple comparisons. Similar results were obtained when the analysis was restricted to women who conceived a DS child before 35 years of age.
LIMITATIONS AND REASONS FOR CAUTION
To the best of our knowledge, this is the first genetic association study aimed at evaluating DNMT3B polymorphisms as maternal risk factors for DS. Replication of the findings in other populations is required.
WIDER IMPLICATIONS OF THE FINDINGS
If confirmed in subsequent studies, DNMT3B promoter polymorphisms might be additional markers to be taken into account when evaluating the contribution of one-carbon (folate) metabolism to the maternal risk of birth of a child with DS.
STUDY FUNDING/COMPETING INTEREST(S)
None of the authors has any competing interest. This work was partially supported by the Italian Ministry of Health and ‘5 per mille’ funding.
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