PurposeGermline WWOX pathogenic variants
have been associated with disorder of sex differentiation (DSD), spinocerebellar
ataxia (SCA), and WWOX-related epileptic
encephalopathy (WOREE syndrome). We review clinical and molecular data on
WWOX-related disorders, further
describing WOREE syndrome and phenotype/genotype correlations.MethodsWe report clinical and molecular findings in 20 additional patients
from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants
in the WWOX gene. Different molecular
screening approaches were used (quantitative polymerase chain reaction/multiplex
ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic
hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome
sequencing), genome sequencing.ResultsTwo copy-number variations (CNVs) or two single-nucleotide
variations (SNVs) were found respectively in four and nine families, with
compound heterozygosity for one SNV and one CNV in five families. Eight novel
missense pathogenic variants have been described. By aggregating our patients
with all cases reported in the literature, 37 patients from 27 families with
WOREE syndrome are known. This review suggests WOREE syndrome is a very severe
epileptic encephalopathy characterized by absence of language development and
acquisition of walking, early-onset drug-resistant seizures, ophthalmological
involvement, and a high likelihood of premature death. The most severe clinical
presentation seems to be associated with null genotypes.ConclusionGermline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic
encephalopathy. We report here the largest cohort of individuals with WOREE
syndrome.
We would like to thank the families for their participation to this study and the members of both the MAIA (http://www.maia-asso.org) and Syndrome de Rokitansky-MRKH (http://asso.orpha.net/MRKH) associations for their contribution. We are also indebted to the physicians involved in the French national PRAM network (Programme de Recherches sur les Aplasies Müllériennes), the GACUA and the GARD research programs. We thank the GIGA Genomics Platform for technical assistance with NGS data generation. This research was supported by funding from the CHU Liège (FIRS), the Walloon Region (WALGEMED project), the University of Liège and the Fond Léon Frédéricq. AJ is supported by the National Fund for Scientific Research, Belgium.
Conflict of Interest statementThe authors declare that they have no conflict of interest.
Ethics approvalThe GARD (genetic alterations in rare diseases) protocol was approved by the UBC Children's and Women's Research Ethics Board (Vancouver, Canada). The GACUA (Identification of genetic factors involved in uterine development by exome sequencing of individuals with hereditary or syndromic uterine and kidney malformation) protocol was approved by the ethics committee from the University Hospital and the University of Liège, Belgium. The PRAM project was approved by the local institutional review board (Comité de Protection des Personnes), and is registered with the French Ministry of Health. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high‐throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3‐year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy‐number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high‐throughput sequencing works as an efficient and cost‐effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.
Purpose
The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.
Methods
Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.
Results
Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID.
Conclusion
We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.
We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy. Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy. Results: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes. Conclusion: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.
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