RESUMEN

BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

Asunto(s)

Acondroplasia , Disostosis Mandibulofacial , Microcefalia , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Ribonucleoproteína Nuclear Pequeña U5 , Humanos , Microcefalia/genética , Microcefalia/diagnóstico , Microcefalia/complicaciones , Femenino , Disostosis Mandibulofacial/genética , Acondroplasia/genética , Acondroplasia/complicaciones , Ribonucleoproteína Nuclear Pequeña U5/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Factores de Elongación de Péptidos/genética , Fenotipo

RESUMEN

Genomic sequencing and clinical genomics have demonstrated that substantial subsets of atypical and/or severe disease presentations result from multilocus pathogenic variation (MPV) causing blended phenotypes. In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in CAPN3 (c.259C > G:p.L87V), MUSK (c.1781C > T:p.A594V), NAV2 (c.1996G > A:p.G666R), and ZC4H2 (c.595A > C:p.N199H). CAPN3, MUSK, and ZC4H2 are established disease genes linked to limb-girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker-Wolff syndrome (WWS; OMIM# 314580), respectively. NAV2 is a retinoic-acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease-contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system-muscle connection. We provide evidence from this n = 1 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease.

Asunto(s)

Distrofia Muscular de Cinturas , Trastornos del Neurodesarrollo , Animales , Calpaína/genética , Egipto , Humanos , Lactante , Proteínas Musculares/genética , Distrofia Muscular de Cinturas/genética , Mutación , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Secuenciación del Exoma

RESUMEN

Genetic disorders can be monogenic or chromosomal. Deletions, duplications, and cryptic imbalances due to rearrangements of the telomeres are seen in a number of patients with psychomotor and language delay. Here, the authors report a case of 1-y-old boy born to nonconsanguineous couple who was evaluated for global developmental delay with phenotypic resemblance to a monogenic disorder namely Robinow syndrome. Cytogenetic microarray showed a double segment imbalance involving chromosome 6p25.3p25.2 and chromosome 8q23.3q24.3. Robinow syndrome also known as fetal face syndrome is a rare disorder with characteristic facial phenotype resembling fetal face with macrocephaly, low-set ears, broad great toes, gum hypertrophy, micropenis, and rhizomelia. Facial features include hypertelorism, wide mouth and short nose with upturned tip. It can have dominant or recessive mode of inheritance. The chromosomal abnormality in this case may provide clue to some novel gene for Robinow syndrome etiology.

Asunto(s)

Deleción Cromosómica , Trisomía , Cromosomas , Anomalías Craneofaciales , Enanismo , Humanos , Deformidades Congénitas de las Extremidades , Masculino , Fenotipo , Trisomía/genética , Anomalías Urogenitales

Asunto(s)

Síndrome de Gitelman , Hipopotasemia , Adulto , Preescolar , Femenino , Genotipo , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/genética , Humanos , Masculino , Herencia Multifactorial , Nefrólogos , Fenotipo

RESUMEN

Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.

Asunto(s)

Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Predisposición Genética a la Enfermedad , Enfermedades Hematológicas/genética , Histona Demetilasas/genética , Proteínas de Neoplasias/genética , Neoplasias del Cuello Uterino/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/epidemiología , Anomalías Múltiples/patología , Adolescente , Adulto , Cara/patología , Femenino , Heterogeneidad Genética , Pruebas Genéticas/métodos , Genotipo , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/epidemiología , Enfermedades Hematológicas/patología , Humanos , Masculino , Mutación , Fenotipo , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Enfermedades Vestibulares/complicaciones , Enfermedades Vestibulares/epidemiología , Enfermedades Vestibulares/patología , Adulto Joven

RESUMEN

We report a family with a spectrum of short stature, craniofacial dysmorphism, and digital anomalies in a father and 2 daughters, with the youngest (proband) displaying a severe phenotype. Clinically, autosomal dominant Robinow syndrome (ADRS) was diagnosed. Whole-exome sequencing identified a heterozygous pathogenic BMP2 variant in the father and his daughters. The phenotype of short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies related to BMP2 haploinsufficiency has some facial and digital resemblance to ADRS. Although this variant segregated in the affected members, it failed to explain the severe phenotype of the proband. A reanalysis of the girl's raw data confirmed 2 disorders: a de novo likely pathogenic DVL1 variant implicated in ADRS and the familial BMP2 variant. A close interplay of high-throughput sequencing and deep phenotyping unraveled the complexities of the blended phenotype in the proband.

RESUMEN

PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

Asunto(s)

Síndrome de Bardet-Biedl , Ciliopatías , Alelos , Síndrome de Bardet-Biedl/genética , Cilios/genética , Ciliopatías/genética , Humanos , Canales de Sodio

RESUMEN

Atypical phenotype of an imprinting disease can develop with a recessive homozygous variant due to uniparental isodisomy. We present a girl with severe intellectual disability, developmental delay, distinctive facial features, and other neuropsychiatric features. Trio whole exome sequencing revealed a novel homozygous frameshift variant in AP4E1 [NM_007347.5:c.2412dupT:p.(Gly805Trpfs*8)] and uniparental isodisomy of chromosome 15 [iUPD(15)]. Single nucleotide polymorphism mapping analysis of exome data showed that the homozygous AP4E1 variant was derived from her heterozygous carrier father and unmasked by paternal iUPD(15). Brain magnetic resonance imaging confirmed the brain abnormalities characteristic of AP4 deficiency including the dilated ventricles and hypointensity in the globus pallidus in susceptibility-weighted imaging. This is the first case report of a combination of AP4E1 deficiency and Angelman syndrome. Our patient indicates that whole exome sequencing could uncover an atypical phenotype caused by multiple genetic factors including the uniparental isodisomy.

Asunto(s)

Síndrome de Angelman , Cromosomas Humanos Par 15/genética , Proteínas de Unión al ADN/deficiencia , Discapacidades del Desarrollo , Trastornos Heredodegenerativos del Sistema Nervioso , Discapacidad Intelectual , Disomía Uniparental/genética , Síndrome de Angelman/genética , Síndrome de Angelman/patología , Síndrome de Angelman/fisiopatología , Preescolar , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Discapacidades del Desarrollo/fisiopatología , Padre , Femenino , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Trastornos Heredodegenerativos del Sistema Nervioso/fisiopatología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Fenotipo , Proteínas de Unión al ARN

RESUMEN

The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.1-16q24.3' caused by uniparental disomy (UPD) that included a maternally inherited homozygous microdeletion covering exon 6 of WWOX (NM_016373.3). mRNA expression analysis revealed that the deletion led to nonsense-mediated decay of the NM_016373.3 transcript; the exon 6 of an alternative transcript (NM_130791.3), lacking the short-chain dehydrogenase, was utilized. The microdeletion in WWOX explains the seizures and intellectual disability, while pathogenic variants in another gene, HSPG2, are likely responsible for the patient's skeletal abnormalities. This report describes a rare autosomal recessive disorder with multiple genetic etiologies, one of which involves UPD.

Asunto(s)

Deleción Cromosómica , Espasmos Infantiles/genética , Proteínas Supresoras de Tumor/genética , Disomía Uniparental/genética , Oxidorreductasa que Contiene Dominios WW/genética , Adulto , Secuencia de Bases , Niño , Cromosomas Humanos Par 16/genética , Femenino , Proteoglicanos de Heparán Sulfato/genética , Homocigoto , Humanos , Lactante , Polimorfismo de Nucleótido Simple/genética

RESUMEN

We report a 29 week fetus with arthrogryposis multiplex congenita, multiple joint dislocations, scoliosis and dysmorphism who was detected to be double heterozygote for putatively pathogenic FBN1 (NM_000138.4:c.6004C > T; p.Pro2002Ser) and FBN2 (NM_001999.3:c.2945G > T; p.Cys982Phe) variants on exome sequencing. The de-novo status of these variants is not confirmed as parental genotypes could not be ascertained. A comparison of the post-mortem findings of the fetus with reported phenotypes of Beals and Marfan syndromes indicated overlapping clinical features suggestive of a blended phenotype.

Asunto(s)

Enfermedades del Tejido Conjuntivo/genética , Fibrilina-1/genética , Fibrilina-2/genética , Anomalías Múltiples/genética , Aracnodactilia/genética , Artrogriposis/genética , Contractura/genética , Exoma/genética , Feto , Heterocigoto , Humanos , Luxaciones Articulares/genética , Fenotipo , Escoliosis/genética , Análisis de Secuencia de ADN

RESUMEN

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

Asunto(s)

Hiperventilación/genética , Discapacidad Intelectual/genética , Patología Molecular , Síndrome de Prader-Willi/genética , Factor de Transcripción 4/genética , Adolescente , Secuencia de Bases/genética , Niño , Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Hibridación Genómica Comparativa , Exoma/genética , Facies , Femenino , Humanos , Hiperventilación/diagnóstico , Hiperventilación/fisiopatología , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/fisiopatología , Obesidad/diagnóstico , Obesidad/genética , Obesidad/fisiopatología , Fenotipo , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/fisiopatología , Gemelos Monocigóticos

RESUMEN

With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these "mendelizing" disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8+ T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in ZAP70. Biallelic mutations in ZAP70 are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous RNF168 variant of unknown significance. RNF168 deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.