Search for a gene responsible for Floating‐Harbor syndrome on chromosome 12q15q21.1
Estelle LopezPatrick CallierValérie Cormier‐DaireDidier LacombeAnne MonclaArmand BottaniSandy LambertAlice GoldenbergBérénice DoraySylvie OdentDamien SanlavilleLucie GueneauLaurence DuplombFrédéric HuetBernard AralChristel Thauvin‐RobinetLaurence Faivre
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Abstract Floating‐Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7 Mb de novo 12q15‐q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array‐CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high‐throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15‐q21.1 microdeletions argue in favor of the phenocopy hypothesis. © 2012 Wiley Periodicals, Inc.Keywords:
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Preclinical models of neurodevelopmental disorders typically use single inbred strains which fail to capture human genetic and symptom heterogeneity that is common clinically. We tested if systematically modeling human genetic diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, Chd8. Trait disruptions mimicked those seen in human populations, including high penetrance of macrocephaly and disrupted behavior, but with robust strain and sex differences. For every trait, some strains exhibited a range of large effect size disruptions, sometimes in opposite directions, and remarkably others expressed resilience. Thus, systematically introducing genetic diversity into mouse models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies and improved treatments.Funding Information: National Institute of Mental Health grant R21MH118685 (P.L., A.K.) National Science Foundation Postdoctoral Research Fellowship in Biology grant 2011039 (M.T.), The Saban Research Institute Research Career Development Fellowship (M.T.), Simms Mann Chair in Developmental Neurogenetics and Developmental Neuroscience and Neurogenetics Program, Children’s Hospital Los Angeles (P.L.), and WM Keck Chair in Neurogenetics, Keck School of Medicine of the University of Southern California (P.L.).Declaration of Interests: Authors declare that they have no competing interests.Ethics Approval Statement: All experimental procedures were approved by the University of Southern California (USC) Institutional Animal Care and Use Committee under protocol 11844-CR011. In addition, all experimental procedures followed the Guidelines for the Care and Use of Laboratory Animals by the National Institutes of Health.
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Abstract Floating‐Harbor syndrome (FHS) is characterized by characteristic facial dysmorphism, short stature with delayed bone age, and expressive language delay. To date, the gene(s) responsible for FHS is (are) unknown and the diagnosis is only made on the basis of the clinical phenotype. The majority of cases appeared to be sporadic but rare cases following autosomal dominant inheritance have been reported. We identified a 4.7 Mb de novo 12q15‐q21.1 microdeletion in a patient with FHS and intellectual deficiency. Pangenomic 244K array‐CGH performed in a series of 12 patients with FHS failed to identify overlapping deletions. We hypothesized that FHS is caused by haploinsufficiency of one of the 19 genes or predictions located in the deletion found in our index patient. Since none of them appeared to be good candidate gene by their function, a high‐throughput sequencing approach of the region of interest was used in eight FHS patients. No pathogenic mutation was found in these patients. This approach failed to identify the gene responsible for FHS, and this can be explained by at least four reasons: (i) our index patient could be a phenocopy of FHS; (ii) the disease may be clinically heterogeneous (since the diagnosis relies exclusively on clinical features), (iii) these could be genetic heterogeneity of the disease, (iv) the patient could carry a mutation in a gene located elsewhere. Recent descriptions of patients with 12q15‐q21.1 microdeletions argue in favor of the phenocopy hypothesis. © 2012 Wiley Periodicals, Inc.
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Candidate gene
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Context: Short stature in children is a common reason for referral to pediatric endocrinologists. The underlying cause of short stature remains unclear in many cases and patients often receive unsatisfactory, descriptive diagnoses. While textbooks underline the rarity of genetic causes of growth hormone (GH) insensitivity and the severity of its associated growth failure, increased genetic testing in patients with short stature of unclear origin has revealed gene defects in the GH/insulin-like growth factor (IGF-I) axis associated with milder phenotypes. As such, heterozygous IGF1 gene defects have been reported as a cause of mild and severe short stature. Here, we aimed to describe the clinical and hormonal profile of children with IGF1 haploinsufficiency and their short-term response to growth hormone treatment (GHT). Case descriptions: We describe five patients presenting with short stature, microcephaly, and in four out of five born small for gestational age diagnosed with IGF1 haploinsufficiency. The phenotype of these patients resembles that of previously described cases with similar gene defects. In our series, segregation of the short stature with the IGF1 deletion is evident from the pedigrees and our data suggests a modest response to GHT. Conclusions: This study is the first case series of complete heterozygous IGF1 deletions in children. The specific genetic defects provide a clear image of the phenotype of IGF1 haploinsufficiency – unbiased by heterozygous mutations with possible dominant negative effects on IGF-I function. We increase the evidence for IGF1 haploinsufficiency as a cause of short stature, microcephaly, and SGA.
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Twelve patients with different features of Turner syndrome, and with Xp and Yp rearrangements involving the pseudoautosomal region (PAR1) are described. In all patients, FISH analysis showed loss of one copy of the Short Stature Homeobox (SHOX)-containing gene. Ten patients had short stature and one disproportionate (mesomelic) normal stature, while the last one had normal stature. Skeletal abnormalities, including shortened ulna, were detected in nine subjects, and in six of them Madelung deformity was observed. These clinical data indicated a genotype phenotype correlation between haploinsufficiency of SHOX, and short stature and skeletal abnormalities.
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Idiopathic short stature
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Heterozygous SHOX defects are observed in about 50 to 90% of patients with Leri-Weill dyschondrosteosis (LWD), a common dominant inherited skeletal dysplasia; and in 2 to 15% of children with idiopathic short stature (ISS), indicating that SHOX defects are the most important monogenetic cause of short stature. In addition, children selected by disproportionate idiopathic short stature had a higher frequency of SHOX mutations (22%). A careful clinical evaluation of family members with short stature is recommended since it usually revealed LWD patients in families first classified as having ISS or familial short stature. SHOX-molecular analysis is indicated in families with LWD and ISS children with disproportionate short stature. Treatment with recombinant human growth hormone is considered an accepted approach to treat short stature associated with isolated SHOX defect. Here we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.
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Idiopathic short stature
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Koolen‐de Vries Syndrome (KdVS), also referred to as 17q21.31 microdeletion syndrome, is caused by haploinsufficiency of the KANSL1 gene. This genetic disorder is associated with a clinical phenotype including facial dysmorphism, developmental delay, and friendly disposition, as well as mild‐to‐moderate intellectual disability. We present the case of a 10 year 8 month old female with KdVS due to a de novo intragenic KANSL1 mutation. At this time, she does not present with intellectual disability, and her verbal intelligence is relatively preserved, although she has perceptual deficits, developmental dyspraxia, and severe speech disorder. This case expands the mild end of the neurodevelopmental spectrum seen in children with de novo KANSL1 mutation and KdVS. © 2017 Wiley Periodicals, Inc.
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Facial dysmorphism
Borderline intellectual functioning
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Idiopathic short stature
Pseudoautosomal region
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<b><i>Introduction:</i></b> Short stature homeobox-containing gene (<i>SHOX</i>) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of <i>SHOX</i> haploinsufficiency. <b><i>Methods:</i></b> We analyzed 51 children with <i>SHOX</i> variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. <b><i>Results:</i></b> Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect <i>SHOX</i> haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. <b><i>Conclusion:</i></b> Novel clinical criteria for screening for <i>SHOX</i> haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.
Haploinsufficiency
Idiopathic short stature
Human genetics
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Haploinsufficiency
Idiopathic short stature
Pseudoautosomal region
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