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1.
Eur J Hum Genet ; 31(8): 905-917, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37188825

RESUMEN

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement.


Asunto(s)
Discapacidad Intelectual , Trastornos del Movimiento , Humanos , Progresión de la Enfermedad , Fibrosis , Células HEK293 , Discapacidad Intelectual/genética , Fenotipo , Convulsiones/genética , Síndrome
2.
Nat Genet ; 54(10): 1534-1543, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36195757

RESUMEN

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the 'X-gate', a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.


Asunto(s)
Mutación con Ganancia de Función , Síndromes de la Apnea del Sueño , Niño , Discapacidades del Desarrollo , Humanos , Mutación/genética , Proteínas del Tejido Nervioso , Canales de Potasio de Dominio Poro en Tándem , Síndromes de la Apnea del Sueño/genética
3.
Am J Med Genet A ; 185(9): 2719-2738, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34087052

RESUMEN

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.


Asunto(s)
Encéfalo/anomalías , Ciclina D2/genética , Hidrocefalia/patología , Megalencefalia/patología , Mutación , Polidactilia/patología , Polimicrogiria/patología , Adolescente , Adulto , Niño , Femenino , Humanos , Hidrocefalia/genética , Lactante , Masculino , Megalencefalia/genética , Polidactilia/genética , Polimicrogiria/genética
4.
Am J Med Genet A ; 185(10): 2863-2872, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34050707

RESUMEN

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23). The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA. Our cohort of patients, gathered through GeneMatcher, exhibited features including tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The individuals presented in this article provide evidence of a syndrome related to alterations in DDX23 characterized predominantly by atypical neurodevelopment.


Asunto(s)
Trastorno del Espectro Autista/genética , ARN Helicasas DEAD-box/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/fisiopatología , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Inestabilidad Genómica/genética , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/fisiopatología , Masculino , Mutación Missense/genética , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/fisiopatología , Empalme del ARN/genética , ARN Bicatenario/genética , Convulsiones/complicaciones , Convulsiones/genética , Convulsiones/fisiopatología
6.
BMC Cancer ; 19(1): 396, 2019 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-31029168

RESUMEN

BACKGROUND: With the introduction of Olaparib treatment for BRCA-deficient recurrent ovarian cancer, testing for somatic and/or germline mutations in BRCA1/2 genes in tumor tissues became essential for treatment decisions. In most cases only formalin-fixed paraffin-embedded (FFPE) samples, containing fragmented and chemically modified DNA of minor quality, are available. Thus, multiplex PCR-based sequencing is most commonly applied in routine molecular testing, which is predominantly focused on the identification of known hot spot mutations in oncogenes. METHODS: We compared the overall performance of an adjusted targeted capture-based enrichment protocol and a multiplex PCR-based approach for calling of pathogenic SNVs and InDels using DNA extracted from 13 FFPE tissue samples. We further applied both strategies to seven blood samples and five matched FFPE tumor tissues of patients with known germline exon-spanning deletions and gene-wide duplications in BRCA1/2 to evaluate CNV detection based solely on panel NGS data. Finally, we analyzed DNA from FFPE tissues of 11 index patients from families suspected of having hereditary breast and ovarian cancer, of whom no blood samples were available for testing, in order to identify underlying pathogenic germline BRCA1/2 mutations. RESULTS: The multiplex PCR-based protocol produced inhomogeneous coverage among targets of each sample and between samples as well as sporadic amplicon drop out, leading to insufficiently or non-covered nucleotides, which subsequently hindered variant detection. This protocol further led to detection of PCR-artifacts that could easily have been misinterpreted as pathogenic mutations. No such limitations were observed by application of an adjusted targeted capture-based protocol, which allowed for CNV calling with 86% sensitivity and 100% specificity. All pathogenic CNVs were confirmed in the five matched FFPE tumor samples from patients carrying known pathogenic germline mutations and we additionally identified somatic loss of the second allele in BRCA1/2. Furthermore we detected pathogenic BRCA1/2 variants in four the eleven FFPE samples from patients of whom no blood was available for analysis. CONCLUSIONS: We demonstrate that an adjusted targeted capture-based enrichment protocol is superior to commonly applied multiplex PCR-based protocols for reliable BRCA1/2 variant detection, including CNV-detection, using FFPE tumor samples.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Ováricas/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Variaciones en el Número de Copia de ADN/genética , Femenino , Formaldehído/química , Humanos , Mutación INDEL , Masculino , Reacción en Cadena de la Polimerasa Multiplex/métodos , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Adhesión en Parafina , Linaje , Reproducibilidad de los Resultados , Fijación del Tejido
7.
Clin Cancer Res ; 25(10): 3152-3163, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30670494

RESUMEN

PURPOSE: The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein-mediated molecular mechanisms of tumor radioresistance. EXPERIMENTAL DESIGN: CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC). RESULTS: High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. CONCLUSIONS: We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.


Asunto(s)
Cadena Pesada de la Proteína-1 Reguladora de Fusión/genética , Tolerancia a Radiación/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Aminoácidos/metabolismo , Transporte Biológico , Biomarcadores de Tumor , Línea Celular Tumoral , Quimioradioterapia , Ciclo del Ácido Cítrico , Cadena Pesada de la Proteína-1 Reguladora de Fusión/metabolismo , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Transportador de Aminoácidos Neutros Grandes 1/genética , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Estrés Oxidativo/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia
8.
Eur J Med Genet ; 62(1): 70-72, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29758292

RESUMEN

Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the phenotype of patients with PPM1D mutations.


Asunto(s)
Anomalías Múltiples/genética , Enfermedades Gastrointestinales/genética , Discapacidad Intelectual/genética , Mutación , Umbral del Dolor , Fenotipo , Proteína Fosfatasa 2C/genética , Anomalías Múltiples/patología , Niño , Enfermedades Gastrointestinales/patología , Humanos , Discapacidad Intelectual/patología , Masculino , Síndrome
9.
PLoS One ; 13(8): e0201041, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30091983

RESUMEN

Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.


Asunto(s)
Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Secuenciación del Exoma/métodos , Exoma/genética , Anomalías Múltiples/genética , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Variación Genética , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación , Malformaciones del Sistema Nervioso/genética , Fenotipo , Embarazo , Análisis de Secuencia de ADN , Síndrome
10.
Ophthalmic Genet ; 39(5): 645-647, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30058938

RESUMEN

Posterior amorphous corneal dystrophy (PACD) (OMIM 612868) is a rare autosomal dominant disorder characterized by partial or complete posterior lamellar corneal opacification, decreased corneal thickness and flattening of the corneal curvature. PACD is associated with heterozygous deletions in chromosome band 12q21.33 harboring DCN, KERA, LUM, and EPYC which encode small leucine-rich proteoglycans. We report on a 7-year-old male patient with PACD who had an interstitial deletion of 1.3 Mb in 12q21.33. His mother carried a balanced insertional translocation involving this 12q21.33 segment which was inserted into the proximal part of the long arm of one chromosome 13. The patient corroborates previous observations that PACD is a contiguous gene syndrome caused by combined haploinsufficiency of DCN, KERA, LUM, and EPYC and provides the first example of a balanced chromosome rearrangement involving 12q21.33 in an unaffected parent.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 12 , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/patología , Haploinsuficiencia , Proteoglicanos Pequeños Ricos en Leucina/genética , Niño , Decorina/genética , Humanos , Lumican/genética , Masculino , Pronóstico , Proteoglicanos/genética
11.
Am J Med Genet A ; 173(10): 2736-2742, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28742244

RESUMEN

Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.


Asunto(s)
Cara/anomalías , Mutación con Ganancia de Función , Hiperuricemia/congénito , Hiperuricemia/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Niño , Cara/patología , Humanos , Hiperuricemia/patología , Masculino , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , Ribosa-Fosfato Pirofosfoquinasa/metabolismo
12.
Clin Dysmorphol ; 26(4): 205-208, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28562391

RESUMEN

Pierpont syndrome (OMIM #602342) is a rare disorder characterized by developmental delay, characteristic facial gestalt, hearing loss, and abnormal fat distribution in the distal limbs. A specific mutation in TBL1XR1 [c.1337A>G; p.(Tyr446Cys)] has been described recently in six unrelated patients with Pierpont syndrome. We report on a male child with developmental delay, distinctive facial dysmorphic features, dystrophy, and abnormal fat distribution in the feet, in whom we identified the identical TBL1XR1 mutation. This patient also had additional clinical features including microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus, and peripheral joint laxity, which had not been reported previously in association with Pierpont syndrome. This patient corroborates the assumption that Pierpont syndrome is exclusively caused by the specific TBL1XR1 missense mutation p.(Tyr446Cys) and the additional features broaden the phenotypic spectrum of this rare disorder.


Asunto(s)
Anomalías Múltiples/patología , Preescolar , Humanos , Lactante , Recién Nacido , Masculino , Síndrome
13.
Clin Endocrinol (Oxf) ; 84(1): 141-8, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26119484

RESUMEN

OBJECTIVE: Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder with loss of subcutaneous adipose tissue at the extremities and metabolic complications such as insulin resistance, hypertriglyceridaemia and hypertension. The aim of this study was to characterize the molecular basis of a family of 5 affected members with FPLD3. METHODS: A 61-year-old female index patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequence analysis of the LMNA and PPARG gene was performed. Structure analysis of the identified mutation was carried out using published X-ray crystal structures. RESULTS: A novel heterozygous PPARG mutation c.1040A>C was identified in all 5 patients of the family but not in unaffected controls. The resulting amino acid substitution p.Lys347Thr is located at the ligand-binding domain (LBD) of the protein and is predicted to disrupt critical molecular interactions to the helix 12 of the LBD. CONCLUSIONS: A novel PPARG mutation leading to FPLD3 is described. The results emphasize the importance of the clinical diagnosis and of further molecular genetic analyses in patients with clinical signs of FPLD but unremarkable LMNA findings.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Lipodistrofia Parcial Familiar/genética , Mutación Missense , PPAR gamma/genética , Adulto , Secuencia de Bases , Cristalografía por Rayos X , Análisis Mutacional de ADN/métodos , Salud de la Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , PPAR gamma/química , Linaje , Conformación Proteica
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