Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number ...variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported.
This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria.
Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size.
This study's high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.
WWOX has been recently implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy (EOEE). By array comparative genomic hybridization, we ...identified a 0.6 Mb homozygous deletion in 16q23.1 in a fetus presenting with brain anomalies. His older sister who died at the age of 22 months from an EOEE was also homozygous for the copy number variations in 16q23.1. This deletion includes the first six exons of WWOX and results in a null genotype in homozygous patients. This family gives additional support for the implication of WWOX in severe EOEEs. We report for the first time prenatal ultrasound findings in a fetus with a WWOX-null genotype. Our study expands the range of brain abnormalities in WWOX-related EOEEs. This additional family confirms the genotype-phenotype correlation with WWOX-null alleles associated with the most severe form of WWOX-related epileptic encephalopathy with premature death.
In clinical exome sequencing (cES), the American College of Medical Genetics and Genomics recommends limiting variant interpretation to established human-disease genes. The diagnostic yield of cES in ...intellectual disability and/or multiple congenital anomalies (ID/MCA) is currently about 30%. Though the results may seem acceptable for rare diseases, they mean that 70% of affected individuals remain genetically undiagnosed. Further analysis extended to all mutated genes in a research environment is a valuable strategy for improving diagnostic yields. This study presents the results of systematic research reanalysis of negative cES in a cohort of 313 individuals with ID/MCA. We identified 17 new genes not related to human disease, implicated 22 non-OMIM disease-causing genes recently or previously rarely related to disease, and described 1 new phenotype associated with a known gene. Twenty-six candidate genes were identified and are waiting for future recurrence. Overall, we diagnose 15% of the individuals with initial negative cES, increasing the diagnostic yield from 30% to more than 40% (or 46% if strong candidate genes are considered). This study demonstrates the power of such extended research reanalysis to increase scientific knowledge of rare diseases. These novel findings can then be applied in the field of diagnostics.
JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic ...features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
Cornelia de Lange syndrome (CdLS; MIM# 122470) is a rare developmental disorder. Pathogenic variants in 5 genes explain approximately 50% cases, leaving the other 50% unsolved. We performed whole ...genome sequencing (WGS) ± RNA sequencing (RNA‐seq) in 5 unsolved trios fulfilling the following criteria: (i) clinical diagnosis of classic CdLS, (ii) negative gene panel sequencing from blood and saliva‐isolated DNA, (iii) unaffected parents' DNA samples available and (iv) proband's blood‐isolated RNA available. A pathogenic de novo mutation (DNM) was observed in a CdLS differential diagnosis gene in 3/5 patients, namely POU3F3, SPEN, and TAF1. In the other two, we identified two distinct deep intronic DNM in NIPBL predicted to create a novel splice site. RT‐PCRs and RNA‐Seq showed aberrant transcripts leading to the creation of a novel frameshift exon. Our findings suggest the relevance of WGS in unsolved suspected CdLS cases and that deep intronic variants may account for a proportion of them.
Whole genome sequencing and RNA sequencing performed in 5 classical Cornelia de Lange syndrome patients, revealing deep intronic NIPBL de novo mutations and differential diagnoses.
Bi‐allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the “AP4 deficiency syndrome.” Core features include hypotonia that progresses to hypertonia and ...spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012C>T p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single‐nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.
In this study we report three new unrelated patients from Middle‐East consanguineous families carrying the previously described NM_004722.4(AP4M1):c.1012C〉T homozygous nonsense variant. We describe their phenotype, and provide evidence that the subjects carrying this variant originate from a common ancestor.
We report here two new familial cases of associated del15q11 and del7p22, with the latter underlining the clinical variability of this deletion. Two siblings patients presented a similar familial ...imbalanced translocation, originating from a balanced maternal translocation, with deletions of 7p22 and of 15q11 arrGRCh37 7p22.3-p22.2(42976-3736851)x1, 15q11.1-q11.2(20172544-24979427)x1.
We used aCGH array, FISH, and karyotype for studying the phenotype of the two patients.
The 7p22 deletion (3.5 Mb) contained 58 genes, including several OMIM genes. Patients 1 and 2 exhibited acquisition delays, morphological particularities, and hypogammaglobulinemia, which was more severe in patient 1. Patient 1 presented also with cerebral vasculitis.
We discuss here how the PDGFa, CARD11, LFNG, GPER1, and MAFK genes, included in the deletion 7p22, could be involved in the clinical and biological features of the two patients.
Background
Bardet–Biedl syndrome (BBS) is a multisystemic disorder characterized by rod–cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic ...hypogonadism, complex female genitourinary malformations, and renal abnormalities. There is a large clinical and also genetic heterogeneity in BBS. Here, we report a patient with polydactyly, hyperechogenic kidneys increased in size with normal corticomedullary differentiation, anal imperforation, and malformation of genitals with presence of a genital tubercle with ventral urethral meatus associated with two unfused lateral genital swelling and absent urethral folds, in the context of 46, XY karyotype.
Methods
Karyotype and solo exome sequencing were performed to look for a genetic etiology for the features described in our patient.
Results
We identified a homozygous in‐frame deletion of exons 4 to 6 in the BBS4 gene (NM‐033028 (BBS4‐i001): c.(157‐?)_(405 +?)del p.(Ala53‐Trp135del), which is classified as pathogenic variant. This analysis allowed the molecular diagnosis of BBS type 4 in this patient.
Conclusion
Complex genital malformations are only reported in female BBS6 patients yet, and genital abnormalities and anal imperforation are not reported in male BBS4 patients to date. We discuss the possible hypotheses for this phenotype, including the phenotypic overlap between ciliopathies.
Here, we report a patient with polydactyly, renal particularities, anal imperforation, and malformation of genitals in the context of 46,XY karyotype. Complex genital malformation and anal imperforation are not reported in male BBS4 patient to date. We discuss the possible hypotheses for this phenotype, including the phenotypic overlap between ciliopathies.
Background
STUB1
has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in
STUB1
are now ...considered a frequent cause of cerebellar ataxia.
Objective
We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.
Methods
Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).
Results
Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with
STUB1
-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).
Conclusion
Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with
STUB1
pathogenic variations, we insist on the difficulty of genetic counselling in
STUB1
-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
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