The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Al-Qattan, Sarah M.; Wakil, Salma M.; Anazi, Shamsa; Alazami, Anas M.; Patel, Nisha; Shaheen, Ranad; Shamseldin, Hanan E.; Hagos, Samya; Al-Dossari, Haya; Salih, Mustafa A.; Khashab, Heba Y. El; Kentab, Amal Y.; Al-Nasser, Mohammed N.; Bashiri, Fahad A.; Kaya, Namik; Alkuraya, Fowzan S.

doi:10.1038/gim.2014.184

Cited by 20 publications

(14 citation statements)

References 31 publications

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“…Other investigators have described the occurrence of de novo variants in consanguineous populations. 20–22 These findings support the hypothesis that recently arisen, private variants play a substantial role in human disease. 23 …”

Section: Discussionsupporting

confidence: 76%

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Posey¹,

Harel²,

et al. 2017

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BACKGROUND Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. METHODS We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. RESULTS A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P = 1.77×10−7). CONCLUSIONS In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.)

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Section: Discussionsupporting

confidence: 76%

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Posey¹,

Harel²,

et al. 2017

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“…Those with a 14q32 deletion are not described with a high‐pitched voice or eczema seen as early hallmark features of DS. Recently, in a large study of the use of molecular karyotyping in patients with consanguineous parents, another child was reported with a 14q32 deletion and “Dubowitz‐like” features, but limited information is available to draw further conclusions (Al‐Qattan et al, ). There are dozens of genes within the 14q32 region that are likely contributing to the phenotype, so it is difficult to define a clear genotype–phenotype correlation (Table ).…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

2018

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Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next‐generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data‐sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome‐wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.

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“…Karyotype revealed 46,XY,del(7)(p21), t(7;13)(q24.1;q22) whereas parental karyotypes were normal. Molecular karyotyping was performed as described previously [Al‐Qattan et al, ] and confirmed the unbalanced nature of the translocation and revealed a de novo deletion in 7p21.1–22.1 of 11,929 kb (5,798,163–17,727,264) spanning 53 genes, as well as a de novo deletion in chr7q31.31–q31.32 of 2,936 kb (118,692,690–121,628,842) spanning seven genes (Fig. C and Table S1).…”

Section: Clinical Reportsmentioning

confidence: 92%

“…As with other clinically and genetically heterogeneous disorders, the challenge in predicting the underlying mutation based solely on clinical appearance can be significant and calls for diagnostic tools that are comprehensive and agnostic to the phenotype. Molecular karyotyping is one such tool that scans the genome at an ever increasing resolution for copy number aberrations that can cause diseases along the entire phenotypic spectrum [Al‐Qattan et al, ]. This tool is now the recommended first–tier test for children with unexplained cognitive impairment or multiple malformations [Miller et al, ].…”

Section: Introductionmentioning

confidence: 99%

Novel copy number variants and major limb reduction malformation: Report of three cases

Shamseldin

Anazi

Wakil

et al. 2016

American J of Med Genetics Pt A

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Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans.

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The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Cited by 20 publications

References 31 publications

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

Novel copy number variants and major limb reduction malformation: Report of three cases

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