Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the ...molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.
We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.
In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.
Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.
We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource‐limited islands in the West Indies. Due to geographic isolation, ...small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2–3 clinics per year on various islands in the Caribbean. We also organized a week‐long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow‐up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.
Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, ...only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.
Background
Individuals with various sized terminal duplications of chromosome 5p or terminal deletions of chromosome 18q have been described. These aberrations may cause congenital malformations and ...intellectual disability of varying severity.
Methods
Via an international collaborative effort, we obtained a cytogenetic diagnosis for a 5‐year‐old boy of Afro‐Caribbean ancestry who has global developmental delay, dysmorphology, hypotonia, feeding difficulties, bilateral club feet, and intellectual disability.
Results
Conventional G‐banded karyotyping showed additional chromatin of unknown origin on the long arm of chromosome 18. SNP microarray confirmed the loss of ~6.4 Mb from chromosome 18q: arrhg19 18q22.3‐q23(71,518,518‐77,943,115)x1. The source of the additional chromatin was determined from the microarray to be ~32 Mb from the short arm of chromosome 5 (arrhg19 5p13.3‐p15.33(51,045‐32,062,984)x3). The unbalanced translocation was verified by fluorescent in situ hybridization (FISH). Both parents are healthy and have normal karyotypes suggesting that this abnormality arose de novo in the proband, although gonadal mosaicism in a parent cannot be excluded.
Conclusion
The combination of clinical features in this individual is most likely due to the partial deletion of 18q and partial duplication of 5p, which to our knowledge has not been previously described.
We describe a 5‐year‐old boy who has global developmental delay, dysmorphology, and multiple congenital abnormalities. Karyotype showed additional chromatin on chromosome 18q. Microarray showed an approximate 32 Mb duplication of material from chromosome 5p (partial trisomy), and an approximate 6.2 Mb deletion from chromosome 18q (partial monosomy). FISH confirmed the unbalanced translocation.
It is a matter of course that in high‐income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a ...definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low‐ and middle‐income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource‐limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource‐limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.
Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear ...genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.
What's already known about this topic?Elevated or decreased human chorionic gonadotrophin from second trimester maternal serum screens have been seen in pregnancies affected with 5p deletion syndrome ...(5p−syndrome).Clinical variability does exist for 5p−syndrome, although the more severe, classic presentation is best described with limited descriptions available for milder presentations.
What does this study add?Analyte values were normal in this case that suggests that normal fetal anatomy and maternal serum analytes may be present in the second trimester of pregnancy in cases of 5p−syndrome.It is important to further define the mild end of the 5p−phenotypic spectrum that may allow increased recognition of previously undiagnosed, affected individuals.
Background
Cornelia de Lange syndrome (CdLS) comprises a recognizable pattern of multiple congenital anomalies caused by variants of the DNA cohesion complex. Affected individuals may display a wide ...range of phenotypic severity, even within the same family.
Methods
Exome sequencing and confirmatory Sanger sequencing showed the same previously described p.Arg629Ter NIPBL variant in two half‐brothers affected with CdLS. Clinical evaluations were obtained in a pro bono genetics clinic.
Results
One brother had relatively mild proportionate limb shortening; the other had complete bilateral hypogenesis of the upper arm with absence of lower arm structures, terminal transverse defects, and no digit remnants. His complex lower limb presentation included long bone deficiency and a deviated left foot. The mother had intellectual disability and microcephaly but lacked facial features diagnostic of the CdLS.
Conclusion
We describe a collaboration between a pediatrics team from a resource‐limited nation and USA‐based medical geneticists. Reports describing individuals of West Indian ancestry are rarely found in the medical literature. Here, we present a family of Afro‐Caribbean ancestry with CdLS presenting with phenotypic variability, including unusual lower limb abnormalities. The observation of this novel family adds to our knowledge of the phenotypic and molecular aspects of CdLS.
We found the same pathogenic NIPBL variant in two half‐brothers who are of Afro‐Caribbean ancestry. One of the brothers has a novel lower limb presentation.
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