SpliceAI is an open-source deep learning splicing prediction algorithm that has demonstrated in the past few years its high ability to predict splicing defects caused by DNA variations. However, its ...outputs present several drawbacks: (1) although the numerical values are very convenient for batch filtering, their precise interpretation can be difficult, (2) the outputs are delta scores which can sometimes mask a severe consequence, and (3) complex delins are most often not handled. We present here SpliceAI-visual, a free online tool based on the SpliceAI algorithm, and show how it complements the traditional SpliceAI analysis. First, SpliceAI-visual manipulates raw scores and not delta scores, as the latter can be misleading in certain circumstances. Second, the outcome of SpliceAI-visual is user-friendly thanks to the graphical presentation. Third, SpliceAI-visual is currently one of the only SpliceAI-derived implementations able to annotate complex variants (e.g., complex delins). We report here the benefits of using SpliceAI-visual and demonstrate its relevance in the assessment/modulation of the PVS1 classification criteria. We also show how SpliceAI-visual can elucidate several complex splicing defects taken from the literature but also from unpublished cases. SpliceAI-visual is available as a Google Colab notebook and has also been fully integrated in a free online variant interpretation tool, MobiDetails ( https://mobidetails.iurc.montp.inserm.fr/MD ).
Two distinct syndromes arise from pathogenic variants in the X-linked gene
BCOR
(BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ...(‘Lenz’-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of
BCOR
null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome (‘Lenz’) usually includes developmental delay in addition to the eye findings and is caused by hypomorphic
BCOR
variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel
BCOR
variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed
BCOR
splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked
BCOR
-related syndrome.
DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve ...interpretation of missense variants, which remains a major challenge in human genetics.
We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature.
This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice.
Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, ...development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.
Hydrops fetalis is a rare disorder associated with significant perinatal complications and a high perinatal mortality of at least 50%. Nonimmune hydrops fetalis (NIHF) is more frequent and results ...from a wide variety of etiologies. One cause of NIHF is lymphatic malformation 6 (LMPHM6) due to biallelic loss‐of‐function (LoF) variants in PIEZO1. Most individuals are diagnosed postnatally and only few clinical data are available on fetal presentations. We report six novel biallelic predicted LoF variants in PIEZO1 identified by exome sequencing in six fetuses and one deceased neonate from four unrelated families affected with LMPHM6. During the pregnancy, most cases are revealed by isolated NIHF at second trimester of gestation. At post‐mortem examination ascites, pleural effusions and telengectasies can guide the etiological diagnosis. We aim to further describe the perinatal presentation of this condition which could be underdiagnosed.
Lymphatic malformation 6 is characterized by a uniform, widespread lymphedema affecting all segments of the body and of varying severity. This condition is due to bi‐allelic loss‐of‐function (LoF) variants in PIEZO1. Up to now, 21 LMPHM6 families have been reported corresponding to 33 affected individuals. Most of LMPHM6 individuals were diagnosed postnatally, with poor clinical data available about fetal presentation. In this manuscript, we further describe the perinatal presentations and/or the autopsies of six fetuses and one neonate from four unrelated families affected with LMPHM6. We also describe six new LoF variants in PIEZO1 identified by exome sequencing.
De novo missense variants in
encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap ...between these two syndromes suggests that they belong to a spectrum of
-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic
variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of
-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.
Congenital hypomyelinating neuropathy is a rare neonatal syndrome responsible for hypotonia and weakness. Nerve microscopic examination shows amyelination or hypomyelination. Recently, mutations in ...CNTNAP1 have been described in a few patients. CNTNAP1 encodes contactin-associated protein 1 (caspr-1), which is an essential component of the paranodal junctions of the peripheral and central nervous systems, and is necessary for the establishment of transverse bands that stabilize paranodal axo-glial junctions. We present the results of nerve biopsy studies of three patients from two unrelated, non-consanguineous families with compound heterozygous CNTNAP1 mutations. The lesions were identical, characterized by a hypomyelinating process; on electron microscopy, we detected, in all nodes of Ranvier, subtle lesions that have never been previously described in human nerves. Transverse bands of the myelin loops were absent, with a loss of attachment between myelin and the axolemma; elongated Schwann cell processes sometimes dissociated the Schwann cell and axon membranes that bound the space between them. These lesions were observed in the area where caspr-1 is located and are reminiscent of the lesions reported in sciatic nerves of caspr-1 null mice. CNTNAP1 mutations appear to induce characteristic ultrastructural lesions of the paranodal region.
WAC‐related intellectual disability (ID) is a rare genetic condition characterized by a spectrum of neurodevelopmental disorders of varying severity, including global developmental delay (GDD), ID, ...and autism spectrum disorder. Here, we describe five affected individuals, age range 9–20 years, and provide proof of pathogenicity of a novel splicing variant. All individuals presented with GDD, some degree of ID, and variable dysmorphism. Except for feeding difficulties, all patients were healthy without major congenital malformations or medical comorbidities. All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC. Three unrelated patients from different ethnic backgrounds shared the intronic variant c.381+4_381+7delAGTA, which was predicted to alter splicing and was initially classified as a variant of uncertain significance. Reverse transcription‐polymerase chain reaction analysis from one patient's cells confirmed aberrant splicing of the WAC transcript resulting in premature termination and a truncated protein p.(Gly92Alafs*2). These functional studies and the identification of several nonrelated individuals provide sufficient evidence to classify this variant as pathogenic. The clinical description of these five individuals and the three novel variants expand the genotypic and phenotypic spectrum of this ultrarare disease.
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