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Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.

Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMO variants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMO variants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMO transcript. Our results confirm bi-allelic SMO variants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.

Background RNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology. Results We developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses. Conclusions PTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available at https://bioinf.eva.mpg.de/PTEE/

[This corrects the article DOI: 10.1371/journal.pone.0201041.].[This corrects the article DOI: 10.1371/journal.pone.0201041.].

Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the “figure 8” shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic “figure 8” shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.

The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. The underlying basis of the variable phenotype remains elusive. We analyzed gene expression using blood from three individuals with 15q13.3 microdeletion and brain cortex tissue from ten mice Df[h15q13]/+. We assessed differentially expressed genes (DEGs), protein–protein interaction (PPI) functional modules, and gene expression in brain developmental stages. The deleted genes’ haploinsufficiency was not transcriptionally compensated, suggesting a dosage effect may contribute to the pathomechanism. DEGs shared between tested individuals and a corresponding mouse model show a significant overlap including genes involved in monogenic neurodevelopmental disorders. Yet, network-wide dysregulatory effects suggest the phenotype is not caused by a single critical gene. A significant proportion of blood DEGs, silenced in adult brain, have maximum expression during the prenatal brain development. Based on DEGs and their PPI partners we identified altered functional modules related to developmental processes, including nervous system development. We show that the 15q13.3 microdeletion has a ubiquitous impact on the transcriptome pattern, especially dysregulation of genes involved in brain development. The high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.

Objective Nigeria, along with other Sub‐Saharan African countries, bears the highest burden of epilepsy worldwide. This high prevalence is attributed to a combination of factors, including a significant incidence of infectious diseases, perinatal complications, and genetic etiologies. Genetic testing is rarely available and is not typically included in the routine diagnostic work‐up for individuals with infantile and childhood epilepsy syndromes in these regions. Exome sequencing (ES) offers a diagnostic yield of 24%–62%, but these figures primarily reflect data from high‐income countries (HICs) and may not be applicable to low‐ and middle‐income countries (LMICs). In this study, we employed ES to investigate the genetic basis of early‐onset epilepsy in 22 affected children from Nigeria. Methods The study involved sampling of patients diagnosed with early‐onset epilepsy syndromes at the Lagos State University Teaching Hospital (LASUTH) Neurology clinic. Venous blood samples were collected, and genomic DNA was isolated and purified. Molecular analysis included DNA fragmentation, ligation, target enrichment, library preparation, and whole‐exome sequencing. Computational analysis involved variant calling, curation, and classification using specialized tools and databases. Results Pathogenic variants were identified in 6 out of 22 individuals, equaling a diagnostic yield of 27.3% and comprising variants in BPTF, NAA15, SCN1A, TUBA1A and twice in CACNA1A. Significance In this study, we present the first exome study on early‐onset epilepsy syndromes from West Africa, facilitated by a Nigerian‐German research collaboration. Our findings reveal a genetic diagnostic yield comparable to that of HICs. The integration of genomic medicine into epilepsy management in Nigeria holds promising prospects for improving patient care and reducing mortality rates. Plain Language Summary This study represents the first published exome findings in Nigerian children with early‐onset epilepsy, revealing a genetic diagnosis in 27% of cases. Pathogenic variants were identified in five genes amongst 6 of 22 patients, underscoring the potential of genetic testing to enhance epilepsy management in developing nations like Nigeria.

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits ( GRIN1 ) and two GluN2 subunits ( GRIN2A - GRIN2D ). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a +/− and Grin2a −/− mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b ). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a +/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a +/− mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a −/− mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients. Null  GRIN2A human patients display a largely transient seizure burden that resolves with age, which may be attributable to a transient delay in the developmental maturation of parvalbumin-positive interneurons in CA1 as is observed in Grin2a +/− and Grin2a - /- mice.

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype–phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin–eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype–phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration.

Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1 -positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p -value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1 -positive patients. Larger cohorts are needed to confirm these results.