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.
The autosomal dominant Okur–Chung neurodevelopmental syndrome (OCNDS: OMIM #617062) is a rare neurodevelopmental disorder first described in 2016. Features include developmental delay (DD), ...intellectual disability (ID), behavioral problems, hypotonia, language deficits, congenital heart abnormalities, and non‐specific dysmorphic facial features. OCNDS is caused by heterozygous pathogenic variants in CSNK2A1 (OMIM *115440; NM_177559.3). To date, 160 patients have been diagnosed worldwide. The number will likely increase due to the growing use of exome sequencing (ES) and genome sequencing (GS). Here, we describe a novel OCNDS patient carrying a CSNK2A1 variant (NM_177559.3:c.140G>A; NP_808227.1:p.Arg47Gln). Phenotypically, he presented with DD, ID, generalized hypotonia, speech delay, short stature, microcephaly, and dysmorphic features such as low‐set ears, hypertelorism, thin upper lip, and a round face. The patient showed several signs not yet described that may extend the phenotypic spectrum of OCNDS. These include prenatal bilateral clubfeet, exotropia, and peg lateral incisors. However, unlike the majority of descriptions, he did not present sleep disturbance, seizures or gait difficulties. A literature review shows phenotypic heterogeneity for OCNDS, whether these patients have the same variant or not. This case report is an opportunity to refine the phenotype of this syndrome and raise the question of the genotype–phenotype correlation.
Cutis laxa (CL) is a rare connective tissue disorder characterized by wrinkled, abundant and sagging skin, sometimes associated with systemic impairment. Biallelic alterations in latent transforming ...growth factor beta‐binding protein 4 gene (LTBP4) cause autosomal recessive type 1C cutis laxa (ARCL1C, MIM #613177). The present report describes the case of a 17‐months‐old girl with cutis laxa together with a literature review of previous ARCL1C cases. Based on proband main clinical signs (cutis laxa and pulmonary emphysema), clinical exome sequencing (CES) was performed and showed a new nine base‐pairs homozygous in‐frame deletion in LTBP4 gene. RT‐PCR and cDNA Sanger sequencing were performed in order to clarify its impact on RNA. This report demonstrates that a genetic alteration in the EGF‐like 14 domain calcium‐binding motif of LTBP4 gene is likely responsible for cutis laxa in our patient.
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.
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.
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.
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.
Des variations bi-alléliques affectant l’un des 4 gènes codant pour les sous-unités AP4 (AP4B1, AP4E1, AP4M1 et AP4S1) sont responsables d’un phénotype commun « le syndrome de déficience AP4 ».
...L’objectif de ce travail était de décrire le phénotype clinique et radiologique d’une variation d’AP4M1 impliquée dans la paraplégie spastique (PS) autosomique récessive 50 (SPG50).
Dans ce travail nous rapportons trois patients issus de trois familles consanguines non apparentées originaires du Moyen-Orient présentant une même variation non-sens homozygote NM_004722.4(AP4M1) : c.1012C>T p.Arg338* (rs146262009).
Les trois enfants présentent une déficience intellectuelle sévère, une microcéphalie, une épilepsie, une PS progressive et une absence de marche. L’analyse des SNPs montre un haplotype commun en faveur de l’effet fondateur. L’IRM montre des anomalies caractéristiques avec un corps calleux (CC) mince, une microcéphalie pour les trois, ainsi qu’une ventriculomégalie avec configuration colpocéphalique et des anomalies de signal du forceps mineur du CC (signe des « oreilles de grizzly ») pour l’un d’entre eux (Fig. 1).
Jusqu’à présent quatre patients issues de trois autres familles portant cette variation Arg338*AP4M1 avaient été identifiés dans la littérature. La récurrence de la variation Arg338*AP4M1 dans au moins six familles du Moyen-Orient suggère un effet fondateur avec un ancêtre commun très probablement d’origine turque.
L’ensemble de ces patients présentent une symptomatologie sévère avec épilepsie, troubles moteurs progressifs avec incapacité à la marche sans aide. La neuroimagerie est un élément clé du diagnostic.
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