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1.
Am J Med Genet A ; 194(5): e63517, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38149346

RESUMO

Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N-sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosplenomegaly with childhood onset. Here, we report on a 53-year-old male subject initially diagnosed with Usher syndrome for the concurrence of retinitis pigmentosa and sensorineural hearing loss. Clinical exome sequencing identified biallelic missense variants in SGSH, and biochemical assays showed complete deficiency of sulfamidase activity and increased urinary glycosaminoglycan excretion. Reverse phenotyping revealed left ventricle pseudo-hypertrophy, hepatosplenomegaly, bilateral deep white matter hyperintensities upon brain MRI, and decreased cortical metabolic activity by PET-CT. On neuropsychological testing, the proband presented only partial and isolated verbal memory deficits. This case illustrates the power of unbiased, comprehensive genetic testing for the diagnosis of challenging mild or atypical forms of MPS IIIA.


Assuntos
Mucopolissacaridose III , Síndromes de Usher , Masculino , Humanos , Criança , Pessoa de Meia-Idade , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/genética , Hidrolases/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Testes Genéticos , Hepatomegalia/genética
2.
Cells ; 13(13)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38994932

RESUMO

Chromosomal rearrangements can interfere with the disjunction and segregation of other chromosome pairs not involved in the rearrangements, promoting the occurrence of numerical abnormalities in resulting gametes and predisposition to trisomy in offspring. This phenomenon of interference is known as the interchromosomal effect (ICE). Here we report a prenatal case potentially generated by ICE. The first-trimester screening ultrasound of the pregnant woman was normal, but the NIPT indicated a high risk for three copies of chromosome 21, thus suspecting trisomy 21 (T21). After a comprehensive clinical evaluation and genetic counseling, the couple decided to undergo amniocentesis. The prenatal karyotype confirmed T21 but also showed a balanced translocation between the long arm of chromosome 15 (q22) and the long arm of chromosome 22. The parents' karyotypes also showed that the mother had the 15;22 translocation. We reviewed T21 screening methods, and we performed a literature review on ICE, a generally overlooked phenomenon. We observed that ours is the first report of a prenatal case potentially due to ICE derived from the mother. The recurrence risk of aneuploidy in the offspring of translocated individuals is likely slightly increased, but it is not possible to estimate to what extent. In addition to supporting observations, there are still open questions such as, how frequent is ICE? How much is the aneuploidy risk altered by ICE?


Assuntos
Síndrome de Down , Herança Materna , Translocação Genética , Humanos , Feminino , Translocação Genética/genética , Síndrome de Down/genética , Gravidez , Adulto , Herança Materna/genética , Feto , Cromossomos Humanos Par 15/genética
3.
Genes (Basel) ; 15(1)2024 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-38275611

RESUMO

Cranio-lenticulo-sutural dysplasia (CLSD, OMIM #607812) is a rare genetic condition characterized by late-closing fontanels, skeletal defects, dysmorphisms, and congenital cataracts that are caused by bi-allelic or monoallelic variants in the SEC23A gene. Autosomal recessive inheritance (AR-CLSD) has been extensively documented in several cases with homozygous or compound heterozygous variants in SEC23A, whereas autosomal dominant inheritance (AD-CLSD) involving heterozygous inherited variants has been reported just in three patients. The SEC23A gene encodes for one of the main components of a protein coat complex known as coat-protein-complex II (COPII), responsible for the generation of the envelope of the vesicles exported from the endoplasmic reticulum (ER) toward the Golgi complex (GC). AR-CLSD and AD-CLSD exhibit common features, although each form also presents distinctive and peculiar characteristics. Herein, we describe a rare case of a 10-year-old boy with a history of an anterior fontanel that closed only at the age of 9. The patient presents with short proportionate stature, low weight, and neurological impairment, including intellectual disability, global developmental delay, abnormal coordination, dystonia, and motor tics, along with dysmorphisms such as a wide anterior fontanel, hypertelorism, frontal bossing, broad nose, high-arched palate, and micrognathia. Trio clinical exome was performed, and a de novo heterozygous missense variant in SEC23A (p.Arg716Cys) was identified. This is the first reported case of CLSD caused by a de novo heterozygous missense variant in SEC23A presenting specific neurological manifestations never described before. For the first time, we have conducted a comprehensive phenotype-genotype correlation using data from our patient and the eight most well-documented cases in the literature. Our work has allowed us to identify the main specific and characteristic signs of both forms of CLSD (AR-CLSD, AD CLSD), offering valuable insights that can guide physicians in the diagnostic process. Notably, detailed descriptions of neurological features such as intellectual disability, global developmental delay, and motor impairment have not been documented before. Furthermore, our literature overview is crucial in the current landscape of CLSD due to the absence of guidelines for the clinical diagnosis and proper follow-up of these patients, especially during childhood.


Assuntos
Deficiência Intelectual , Proteínas de Transporte Vesicular , Masculino , Humanos , Criança , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Mutação de Sentido Incorreto , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo
4.
Genes (Basel) ; 14(5)2023 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-37239476

RESUMO

The implementation of array comparative genomic hybridisation (array-CGH) allows us to describe new microdeletion/microduplication syndromes which were previously not identified. 9q21.13 microdeletion syndrome is a genetic condition due to the loss of a critical genomic region of approximately 750kb and includes several genes, such as RORB and TRPM6. Here, we report a case of a 7-year-old boy affected by 9q21.13 microdeletion syndrome. He presents with global developmental delay, intellectual disability, autistic behaviour, seizures and facial dysmorphism. Moreover, he has severe myopia, which was previously reported in only another patient with 9q21.13 deletion, and brain anomalies which were never described before in 9q21.13 microdeletion syndrome. We also collect 17 patients from a literature search and 10 cases from DECIPHER database with a total number of 28 patients (including our case). In order to better investigate the four candidate genes RORB, TRPM6, PCSK5, and PRUNE2 for neurological phenotype, we make, for the first time, a classification in four groups of all the collected 28 patients. This classification is based both on the genomic position of the deletions included in the 9q21.3 locus deleted in our patient and on the different involvement of the four-candidate gene. In this way, we compare the clinical problems, the radiological findings, and the dysmorphic features of each group and of all the 28 patients in our article. Moreover, we perform the genotype-phenotype correlation of the 28 patients to better define the syndromic spectrum of 9q21.13 microdeletion syndrome. Finally, we propose a baseline ophthalmological and neurological monitoring of this syndrome.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Masculino , Criança , Deficiências do Desenvolvimento/genética , Deleção Cromossômica , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Estudos de Associação Genética
5.
Genes (Basel) ; 14(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36672860

RESUMO

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder that affects many organs. The diagnosis of this condition is primarily clinical and it can be confirmed by molecular analysis of the genes known to cause this disease, although about 30% of CdLS patients are without a genetic diagnosis. Here we report clinical and genetic findings of a patient with CdLS type 4, a syndrome of which the clinical features of only 30 patients have been previously described in the literature. The index patient presented with clinical characteristics previously associated with CdLS type 4 (short nose, thick eyebrow, global development delay, synophrys, microcephaly, weight < 2DS, small hands, height < 2DS). She also presented cardiac anomalies, cleft palate and laryngomalacia, which was never described before. The index patient was diagnosed with a novel de novo RAD21 variant (c.1722_1723delTG, p.Gly575SerfsTer2): segregation analysis, bioinformatic analysis, population data and in silico structural modelling indicate the pathogenicity of the novel variant. This report summarizes previously reported clinical manifestations of CdLS type 4 but also highlights new clinical symptoms, which will aid correct counselling of future CdLS type 4 cases.


Assuntos
Fissura Palatina , Síndrome de Cornélia de Lange , Hipertricose , Feminino , Humanos , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Proteínas de Ciclo Celular/genética , Fenótipo , Proteínas de Ligação a DNA/genética
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