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1.
Strabismus ; : 1-5, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34709103

RESUMO

We describe a four-year-old girl with bilateral severe iris hypoplasia and secondary ocular hypertension. Genetic testing revealed a de novo deletion in the FOXC1 gene, establishing the diagnosis of Axenfeld-Rieger syndrome (ARS). The girl developed a gradually increasing exotropia, up to 95 prism diopters by the age of 3 years wherefore strabismus surgery was performed. Intra-operatively, only very rudimentary developed medial and lateral rectus muscles were found. This is the first observation of pronounced hypoplasia of both medial and lateral rectus muscles associated with ARS.

3.
Mol Genet Genomic Med ; 9(10): e1797, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34499417

RESUMO

BACKGROUND: KCNMA1 mutations have recently been associated with a wide range of dysmorphological, gastro-intestinal, cardiovascular, and neurological manifestations. METHODS: Whole exome sequencing was performed in order to identify the underlying pathogenic mutation in two cases presenting with diverse phenotypical manifestations that did not fit into well-known clinical entities. RESULTS: In an 8-year-old boy presenting with severe aortic dilatation, facial dysmorphism, and overgrowth at birth a de novo p.Gly375Arg KCNMA1 mutation was identified which has been reported previously in association with gingival hypertrophy, aortic dilatation, and developmental delay. Additionally, in a 30-week-old fetus with severe growth retardation and duodenal atresia a de novo p.Pro805Leu KCNMA1 mutation was identified. The latter has also been reported before in a boy with severe neurological manifestations, including speech delay, developmental delay, and cerebellar dysfunction. CONCLUSION: The current report presents the first antenatal presentation of a pathogenic KCNMA1 mutation and confirms the specific association of the p.Gly375Arg variant with early onset aortic root dilatation, gingival hypertrophy, and neonatal overgrowth.

4.
Mol Genet Genomic Med ; 9(9): e1768, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34402213

RESUMO

BACKGROUND: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. METHODS: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. RESULTS: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. CONCLUSION: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.

5.
PLoS Genet ; 17(7): e1009679, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34324492

RESUMO

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.


Assuntos
Variações do Número de Cópias de DNA/genética , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Bases de Dados Genéticas , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Genômica/métodos , Humanos , Canais Iônicos/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética
6.
Obstet Gynecol ; 137(6): 1102-1108, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33957658

RESUMO

OBJECTIVE: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies. METHODS: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort. RESULTS: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. CONCLUSION: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations.


Assuntos
Síndrome de Down/diagnóstico , Reabsorção do Feto , Teste Pré-Natal não Invasivo , Gravidez Múltipla , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Amniocentese , Âmnio/diagnóstico por imagem , Ácidos Nucleicos Livres/análise , Córion/diagnóstico por imagem , Erros de Diagnóstico , Reações Falso-Negativas , Feminino , Reabsorção do Feto/diagnóstico , Reabsorção do Feto/genética , Genoma Humano , Humanos , Gravidez , Gravidez de Quadrigêmeos , Gravidez de Trigêmeos , Gravidez de Gêmeos , Estudos Retrospectivos , Sensibilidade e Especificidade , Trissomia
7.
EClinicalMedicine ; 35: 100856, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34036251

RESUMO

Background: Implausible false positive results in non-invasive prenatal testing (NIPT) have been occasionally associated with the detection of occult maternal malignancies. Hence, there is a need for approaches allowing accurate prediction of whether the NIPT result is pointing to an underlying malignancy, as well as for organized programs ensuring efficient downstream clinical management of these cases. Methods: Using a data set of 88,294 NIPT performed at University Hospital Leuven (Belgium) between November 2013 and March 2020, we retrospectively evaluated the positive predictive value (PPV) of our NIPT approach for cancer detection. In this approach, whole-genome cell-free DNA (cfDNA) data from NIPT were scrutinized for the presence of (sub)chromosomal copy number alterations (CNAs) predictive for a malignancy, using an unbiased NIPT analysis pipeline coined GIPSeq. For suspected cases, the presence of a maternal cancer was evaluated via subsequent multidisciplinary clinical follow-up examinations. The cancer-specificity of the identified CNAs in cfDNA was assessed through genetic analyses of a tumor biopsy. Findings: Fifteen women without a cancer history were identified with a GIPSeq result suggestive of a malignant process. Their cfDNA profiles showed either genome-wide aberrations or a single trisomy 8. Upon clinical examinations, a solid or hematological cancer was identified in 4 and 7 cases, respectively. Three women were identified as having a clonal mosaicism. For one case no underlying condition was found. These numbers add to a PPV of 73%. Based on this experience, we presented a multidisciplinary care path for efficient clinical management of these cases. Interpretation: The presented approach for analysing NIPT results has a high PPV, yet unknown sensitivity, for detecting asymptomatic malignancies upon routine NIPT. Given the complexity of diagnosing a pregnant woman with cancer, clinical follow-up should occur in a well-designed multidisciplinary setting, such as via the care model that we presented here. Funding: This work was supported by Research Foundation Flanders and KU Leuven funding.

8.
Genet Med ; 23(6): 1137-1142, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33564150

RESUMO

PURPOSE: Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation. METHODS: The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered. RESULTS: Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%. CONCLUSION: Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.


Assuntos
Transtornos Cromossômicos , Síndrome de Down , Teste Pré-Natal não Invasivo , Aneuploidia , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Síndrome de Down/diagnóstico , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Humanos , Gravidez , Diagnóstico Pré-Natal , Trissomia
9.
Cleft Palate Craniofac J ; 58(4): 505-513, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33063524

RESUMO

This case series is a follow-up report focusing on dental and facial characteristics in patients with a rare microdeletion in chromosome 14q22.1-q22.2. Usually, these patients have severe ocular, brain, and digital abnormalities. However, this case series shows that clinical presentation can be mild. Four relatives spanning 3 generations were diagnosed with a familial autosomal dominant 2.79 Mb microdeletion in chromosome 14q22.1-q22.2. Genetic screening was done by the Bacterial Artificial Chromosome array-comparative genome hybridization and was confirmed by the fluorescence in situ hybridization technique. Dental and craniofacial data were collected from medical files, clinical examinations, clinical photos, panoramic and cephalometric radiographs, and dental casts. Written informed consent for scientific use was obtained for all family members. No larger syndrome could be identified. All cases had similar facial red flag characteristics, consisting of a long face with retrognathia and open mouth relation, associated oral clefts in varying degrees, depressed nasal bridge, delayed tooth development, hypertelorism, and low-set angular ears. The dental casts showed a distal molar occlusion and a lack of space in the dental arches. Developmental delay was noted together with limb defects such as poly- and syndactyly. Microphthalmia and hearing loss were present in the most severe cases. This rare congenital disorder, associated with facial dysmorphia, oral clefts, and tooth agenesis, can remain undiagnosed until adulthood. A family history of short stature, developmental delay, poly- or syndactyly, and micropthalmia are suggestive features. Similar reports help to raise awareness among dental practitioners, leading to an early genetic diagnosis.


Assuntos
Odontólogos , Sindactilia , Adulto , Cefalometria , Deleção Cromossômica , Humanos , Hibridização in Situ Fluorescente , Papel Profissional , Sindactilia/genética
10.
Clin Genet ; 99(2): 318-324, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33169370

RESUMO

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

11.
Genet Med ; 23(2): 352-362, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33106617

RESUMO

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.


Assuntos
Deficiência Intelectual , Microcefalia , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/genética , Hipotonia Muscular , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Proteína Fosfatase 2/genética , Fatores de Transcrição
12.
Am J Med Genet A ; 185(2): 453-460, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33247552

RESUMO

In Central-Africa, neonatal infections, asphyxia and prematurity are main reasons for admission to the neonatal intensive care unit and major determinants of newborn survival. Also, the outcome of newborns with congenital anomalies is expected to be poor, due to a lack of state-of-the art care. We conducted a study of 102 newborns recruited in the Neonatal Intensive Care Unit (NICU) at the University Hospitals of Kinshasa, DR Congo, to assess the impact of congenital anomalies. The presence of a major anomaly was associated with a hazard ratio of death of 13.2 (95%CI: 3.7-46.7, p < .001). In addition, the presence of three or more minor anomalies was associated with a 4.5-fold increased risk of death (95%CI: 1.1-18.6, p = .04). We conclude that like major anomalies, the presence of three or more minor anomalies should also be given particular attention and that the evaluation of dysmorphism should be promoted in NICU.


Assuntos
Anormalidades Múltiplas/epidemiologia , Doenças do Recém-Nascido/epidemiologia , Unidades de Terapia Intensiva Neonatal , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , República Democrática do Congo/epidemiologia , Feminino , Hospitalização , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Masculino
13.
Am J Med Genet A ; 185(3): 990-994, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33372375

RESUMO

Xia-Gibbs syndrome (XGS) is a very rare genetic condition. The clinical spectrum is very broad and variable. The phenotype and evolution in a Congolese boy with XGS have been reported. At 6 years he had speech delay, drooling, marked hyperactivity, attention deficit, aggressive behavior, and intellectual disability. Dysmorphological evaluation revealed strabismus, mild unilateral ptosis, uplifted ear lobes, flat philtrum, thin upper lip vermillion, high arched palate, and flat feet. Patient-only whole exome sequencing identified a known pathogenic frameshift variant in the AHDC1 gene [NM_001029882.3(AHDC1):c.1122dupC;(p.Gly375ArgfsTer3)]. The clinical follow-up revealed the deterioration of his fine motor skills and significant cerebellar phenotype including tremor, pes cavus, and gait instability at the age of 12 years. This patient was compared with three previously reported patients with the same variant but did not identify a consistent pattern in the evolution of symptoms with age.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Mutação da Fase de Leitura , Deficiência Intelectual/genética , Agenesia do Corpo Caloso/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , República Democrática do Congo , Face/anormalidades , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Insuficiência da Valva Mitral/genética , Insuficiência da Valva Mitral/cirurgia , Palato/anormalidades , Síndrome , Pé Cavo/genética , Sequenciamento Completo do Exoma
14.
Eur J Med Genet ; 63(11): 104009, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758660

RESUMO

Interstitial 19q13.11 deletions are associated with ectrodactyly, which has recently been linked to loss-of-function of the UBA2 gene. We report a boy with a de novo frameshift mutation in UBA2 (c.612delA (p.(Glu205Lysfs*63)), presenting with ectrodactyly of the feet associated with learning difficulties and minor physical anomalies. We review genotype-phenotype correlations in patients with chromosomal 19q13.11 microdeletions compared to those with intragenic UBA2 mutations.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Deformidades Congênitas dos Membros/genética , Fenótipo , Enzimas Ativadoras de Ubiquitina/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Mutação da Fase de Leitura , Genótipo , Humanos , Deformidades Congênitas dos Membros/patologia , Masculino
15.
Birth Defects Res ; 112(16): 1287-1291, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32639113

RESUMO

BACKGROUND: Agnathia otocephaly is a rare craniofacial malformation complex characterised by absent/hypoplastic mandible, abnormally positioned ears meeting at level of neck. Besides mutations in two genes, PRRX1 and OTX2, a teratogenic cause has been suggested. A higher risk of congenital malformations has been associated with paternal work in mining in the Democratic Republic of the Congo's part of the Copperbelt. CASE: We studied a female neonate with a clinical diagnosis of agnathia otocephaly, stillborn in Lubumbashi in 2019. The child's father had been working as an artisanal mineworker at the time of conception. RESULTS: Genetic analysis did not reveal a causal mutation. The concentrations of cobalt, arsenic cadmium, and uranium in cord blood of the infant were much higher than those of normal neonates from a previous study. CONCLUSION: In the absence of identified genetic causes, we hypothesize this case of agnathia otocephaly was related to an exogenous cause, possibly the father's mining-related job.


Assuntos
Anormalidades Craniofaciais , Anormalidades Maxilomandibulares , Criança , Anormalidades Craniofaciais/induzido quimicamente , Anormalidades Craniofaciais/genética , República Democrática do Congo , Feminino , Proteínas de Homeodomínio , Humanos , Lactente , Recém-Nascido , Zâmbia
16.
J Clin Endocrinol Metab ; 105(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32685970

RESUMO

PURPOSE: In a significant proportion of children born small for gestational age (SGA) with failure of catch-up growth, the etiology of short stature remains unclear after routine diagnostic workup. We wanted to investigate if extensive analysis of the (epi)genome can unravel the cause of growth failure in a significant portion of these children. PATIENTS AND METHODS: Twenty SGA children treated with GH because of short stature were selected from the BELGROW database of the Belgian Society for Pediatric Endocrinology and Diabetology for exome sequencing, single-nucleotide polymorphism (SNP) array and genome-wide methylation analysis to identify the (epi)genetic cause. First-year response to GH was compared with the response of SGA patients in the KIGS database. RESULTS: We identified (likely) pathogenic variants in 4 children (from 3 families) using exome sequencing and found pathogenic copy number variants in 2 probands using SNP array. In a child harboring a NSD1-containing microduplication, we identified a DNA methylation signature that is opposite to the genome-wide DNA methylation signature of Sotos syndrome. Moreover, we observed multilocus imprinting disturbances in 2 children in whom no other genomic alteration could be identified. Five of 6 children with a genetic diagnosis had an "above average" response to GH. CONCLUSIONS: The study indicates that a more advanced approach with deep genotyping can unravel unexpected (epi)genomic alterations in SGA children with persistent growth failure. Most SGA children with a genetic diagnosis had a good response to GH treatment.


Assuntos
Metilação de DNA/genética , Doenças do Recém-Nascido/genética , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Epigenoma , Feminino , Genômica , Humanos , Recém-Nascido , Masculino
17.
Prenat Diagn ; 40(10): 1272-1283, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32436253

RESUMO

OBJECTIVE: Belgian genetic centers established a database containing data on all chromosomal microarrays performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non-benign copy number variant (CNV). METHODS: All children diagnosed with a prenatally detected non-benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social-Emotional Second Edition and a general questionnaire. RESULTS: A significant difference in communication and personal-social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case-by-case manner. CONCLUSION: Our postnatal follow-up project of children with a prenatally detected non-benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings.

18.
Am J Med Genet A ; 182(7): 1572-1575, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32406590

RESUMO

Sotos syndrome is a widely studied overgrowth syndrome. Clinical presentation includes excessive growth during childhood, macrocephaly, learning difficulties of various degrees, variable minor features, and distinctive facial gestalt. We provide in this report the first phenotypic and growth description of Sotos syndrome in a patient from Central Africa. At 6 month the patient exhibited axial hypotonia, delayed speech development and dysmorphism including long face, sparse eyebrows, hypertelorism, malar hypoplasia and dark flushing, short philtrum, depressed nasal root, anteverted nares, thick upper and lower lip vermilions, macroglossia, prominent forehead, large and peculiar ears, wide intermammillary distance, deep palmar creases, dysplastic finger nails, partial syndactyly of toes, broad, and overlapping hallux. At 19 months, malar flushing became reddish and a retraction of the middle of the lower lip was observed, resembling a bifid lip. He retained the same clinical features at 31 months. Head circumference, weight, and height where within normal ranges at birth but became all above 97th centiles at 4 months. The height velocity evolved in three phases starting with a very fast growth from birth to 6 months (54 cm/year), then a fast phase from 6 to 16 months (18 cm/year) and a slow phase from 16 to 31 months (4.8 cm/year). Conversely, the patient exhibited an acceleration of weight after the first year of life. Our patient exhibited very prominent lips and deep philtrum, which are common facial traits in African individuals. The current report shows an admixture of ethnic-specific features with syndrome-specific features in an African patient.


Assuntos
Síndrome de Sotos/etiologia , Peso Corporal , Pré-Escolar , República Democrática do Congo , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Masculino , Hipotonia Muscular/etiologia , Transtornos Psicomotores/etiologia , Síndrome de Sotos/genética , Sindactilia , Dedos do Pé/anormalidades
19.
Eur J Med Genet ; 63(5): 103875, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32058062

RESUMO

The application of next-generation sequencing to fetal pathology has proved to increase the diagnostic yield in fetuses with abnormal ultrasounds. We retrospectively reviewed genetic data of 30 selected cases studied through targeted resequencing of OMIM genes. In our experience, clinical data proved to be essential to support diagnostic reasoning and enhance variants' assessment. The molecular diagnosis was reached in 19/30 (63%) cases. Only in 7/19 cases the molecular diagnosis confirmed the initial diagnostic hypothesis, showing the relevance of the genotype-first approach. According to the genotype-phenotype correlation, we were able to divide the solved cases into three groups: i) the correlation is well established but it was missed due to lack of specificity, unusual presentation or recent description; ii) the clinical presentation is much more severe than currently known for the underlying condition; iii) the correlation does not recapitulate the entire phenotype, possibly due to the fetal presentation or multiple coexisting conditions. Moreover, we found a higher proportion of recessive diagnosis in abnormal fetuses compared to cohorts of individuals with developmental delay. Our findings suggest that fetal pathology may be enriched in rare alleles and/or in unusual combinations, counter-selected in postnatal genomes and thus contributing to both phenotypic extremeness and atypical presentation.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/estatística & dados numéricos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Diagnóstico Pré-Natal/estatística & dados numéricos , Feminino , Feto/patologia , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Humanos , Masculino , Mutação , Análise de Sequência de DNA/estatística & dados numéricos
20.
Am J Med Genet A ; 182(4): 632-639, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31912658

RESUMO

The evaluation of minor physical variation is crucial in a dysmorphological examination. Currently, data on the spectrum and incidence of minor physical variants in Central African newborns is lacking. We therefore conducted a cross-sectional descriptive study of 722 newborns recruited within the first 24 hr of life, in two large maternities in Kinshasa, DR Congo. Minor anomalies were defined according to the series of articles in AJMG Part A and coded as human phenotype ontology terms. A total of 97 different morphological variants were recorded of which 13 were common. About 34.8% of the newborn carried one minor anomaly, 11.6% had two, and 4.3% had three minor anomalies. No gender differences were observed, but the incidence of specific anomalies appeared to vary with the geographical origin of parents within the DR Congo. The results of this study will aid clinicians to interpret morphological variation in Central African newborns.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Adulto , Estudos Transversais , República Democrática do Congo/epidemiologia , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Exame Físico , Adulto Jovem
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