A <scp><i>SOX3</i></scp> duplication and lumbosacral spina bifida in three generations

Butler, Kameryn M.; Fee, Timothy; DuPont, Barbara R.; Dean, Jane H.; Stevenson, Roger E.; Lyons, Michael J.

doi:10.1002/ajmg.a.62668

Cited by 5 publications

(5 citation statements)

References 15 publications

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“…Two copy gain CNVs encompassing SOX3 were found in 2015 and 2017 in our cohort in two fetuses: one duplication in a male fetus presenting with spina bifida (arr [hg19] Xq27.1(139103383_139801281)x2) and a duplication-triplication in a male fetus with acrania (arr [hg19] Xq27.1(139103383-139763381)x2~3). SOX3 duplications are implicated in variable phenotypes, including myelomeningocele in both sexes, intellectual disability (of varying severity), and growth hormone deficiency (including panhypopituitarism) in males [ 41 ]. Hureaux et al, 2019 conducted a study on a fetal cohort showing that these SOX3 gene duplications are involved in neural tube closure defects [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study

Ravel,

Renaud,

Muller

et al. 2023

Genome Med

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Background 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. Methods 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. Results 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. Conclusions 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.

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Section: Resultsmentioning

confidence: 99%

Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study

Ravel,

Renaud,

Muller

et al. 2023

Genome Med

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“…26 In case of isolated NTDs, the precise frequency of chromosomal aberrations has not been established but seems to be less than 5%. 75 The most common polymalformative syndrome and chromosomal disorders associated with open dysraphisms are listed in Table 1. 73,74…”

Section: Despite Bladder and Bowel Dysfunctions Being Common In Chil-mentioning

confidence: 99%

Proposal for standardized prenatal assessment of fetal open dysraphisms by the European reference network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies (ITHACA) and eUROGEN

Guilbaud,

Carreras,

Garel

et al. 2024

Prenatal Diagnosis

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Open dysraphisms, that is, myelomeningocele and myeloschisis, are rare diseases associated with a risk of severe disability, including lower limb motor and sensory deficiency, sphincter deficiency, and potential intellectual deficiency. Open dysraphism is diagnosed in Europe in 93.5% of cases. In case of suspicion of fetal open dysraphism, a detailed fetal morphologic assessment is required to confirm the diagnosis and exclude associated structural anomalies, as well as genetic assessment. In case of isolated fetal open dysraphism, assessment of prognosis is based on fetal imaging including the level of the lesion, the presence or not of a sac, the presence and nature of intra cranial anomalies, and the anatomical and functional evaluation of the lower extremities. Based on these biomarkers, a personalized prognosis as well as comprehensive information about prenatal management alternatives will allow parents to decide on further management options. Standardization of prenatal assessment is essential to compare outcomes with benchmark data and make assessment of surgical innovation possible. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated open dysraphism.

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“…Lumbosacral spina bifida has occurred in males and females with SOX3 duplications, but has not occurred with sequence alterations. 41 3.18 | FMR1 (Xq27.3)…”

Section: Sox3 (Xq26)mentioning

confidence: 99%

“…Duplications of SOX3 as well as pathogenic variants that reduce gene dosage have been associated with intellectual deficit, isolated growth hormone deficiency or panhypopituitarism, short stature, gynecomastia, and incomplete virilization in males. Lumbosacral spina bifida has occurred in males and females with SOX3 duplications, but has not occurred with sequence alterations 41 …”

Section: Duplications Of Xlid Genesmentioning

confidence: 99%

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

Sahajpal,

Ziats,

Chaubey

et al. 2023

Clinical Genetics

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Duplication of all genes associated with X‐linked intellectual disability (XLID) have been reported but the majority of the duplications include more than one XLID gene. It is exceptional for whole XLID gene duplications to cause the same phenotype as sequence variants or deletions of the same gene. Duplication of PLP1, the gene associated with Pelizaeus‐Merzbacher syndrome, is the most notable duplication of this type. More commonly, duplication of XLID genes results in very different phenotypes than sequence alterations or deletions. Duplication of MECP2 is widely recognized as a duplication of this type, but a number of others exist. The phenotypes associated with gene duplications are often milder than those caused by deletions and sequence variants. Among some duplications that are clinically significant, marked skewing of X‐inactivation in female carriers has been observed. This report describes the phenotypic consequences of duplication of 22 individual XLID genes, of which 10 are described for the first time.

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A SOX3 duplication and lumbosacral spina bifida in three generations

Cited by 5 publications

References 15 publications

Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study

Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study

Proposal for standardized prenatal assessment of fetal open dysraphisms by the European reference network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies (ITHACA) and eUROGEN

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

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