| 1. |
- Hu, H., et al.
(författare)
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X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:1, s. 133-148
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Tidskriftsartikel (refereegranskat)abstract
- X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
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| 2. |
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| 3. |
- Parenti, I., et al.
(författare)
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Expanding the clinical spectrum of the "HDAC8-phenotype - implications for molecular diagnostics, counseling and risk prediction
- 2016
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Ingår i: Clinical Genetics. - : WILEY-BLACKWELL. - 0009-9163 .- 1399-0004. ; 89:5, s. 564-573
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Tidskriftsartikel (refereegranskat)abstract
- Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.
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| 4. |
- Simon-Bouy, Brigitte, et al.
(författare)
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Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling.
- 2008
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Ingår i: Prenatal diagnosis. - : Wiley. - 0197-3851 .- 1097-0223. ; 28:11, s. 993-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. METHOD: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. RESULTS: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series. CONCLUSION: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.
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| 5. |
- Concepcion Gil-Rodriguez, Maria, et al.
(författare)
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De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes
- 2015
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Ingår i: Human Mutation. - : Wiley: 12 months. - 1059-7794 .- 1098-1004. ; 36:4, s. 454-462
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Tidskriftsartikel (refereegranskat)abstract
- Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximate to 1%-2% of CdLS-like phenotypes.
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