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1.
J Med Genet ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461977

RESUMO

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted. METHODS: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions. RESULTS: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports. CONCLUSION: We conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.

2.
Am J Med Genet A ; 185(3): 916-922, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33369125

RESUMO

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

3.
Front Pediatr ; 8: 574857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194904

RESUMO

Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth syndromes generally present with inherent health concerns and, in some instances, an increased risk of tumor predisposition that necessitate prompt diagnosis and appropriate referral. In this review, we introduce some of the more common overgrowth syndromes, along with their molecular mechanisms, diagnostics, and medical complications for improved recognition and management of patients affected with these disorders.

4.
Am J Med Genet A ; 182(11): 2751-2754, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32885560

RESUMO

Sudden Infant Death with Dysgenesis of the Testes syndrome (SIDDT) is a very rare condition associated with biallelic pathogenic variants in the TSPYL1 gene first reported in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction, and is uniformly fatal before the age of 12 months. There were previously 21 reported cases of SIDDT in the literature, all from nine Old Order Amish families published in a single paper. In this report, we describe a non-Amish, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Initial testing showed that she had a 46,XY chromosome complement, and chromosomal microarray showed a significant absence of heterozygosity (AOH) totalling roughly 600 Mb across multiple different chromosomes, indicating consanguinity. Further workup with exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52) consistent with a diagnosis of SIDDT, explaining many of her clinical features. However, she was also noted to have a mild T-cell lymphopenia and developed intractable epilepsy after hospital discharge. These features have not previously been reported in SIDDT and may represent phenotypic expansion. To our knowledge, this patient is the 22nd case of SIDDT to be reported in the literature, and the first to be of non-Amish heritage.

5.
Mol Genet Genomic Med ; 8(10): e1383, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32692472

RESUMO

BACKGROUND: CACNA1A variants have been described in several disorders that encompass a wide range of neurologic phenotypes, including hemiplegic migraine, ataxia, cognitive delay, and epilepsy. To date, ischemic stroke caused by a CACNA1A variant has only been reported once in the literature. METHODS: We describe a 4-year-old female with recurrent ischemic strokes beginning at 6 weeks of age, intractable epilepsy, and significant global developmental delay. Exome sequencing (ES) was completed for her evaluation. RESULTS: We found a novel de novo, likely pathogenic variant, p.Leu1692Gln in CACNA1A by ES. The substitution affects a leucine residue that is highly conserved in species from fish to primates. CONCLUSION: We present the second case of recurrent ischemic strokes in a patient with CACNA1A mutation. Our findings expand the phenotypic heterogeneity related to Cav 2.1 (P/Q-type) calcium channel dysfunction and suggest consideration of CACNA1A disorder in evaluation of pediatric strokes.

6.
Am J Hum Genet ; 107(3): 544-554, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730804

RESUMO

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Criança , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Variação Genética/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Locomoção/genética , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , RNA Polimerase II/genética , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , Convulsões/fisiopatologia , Sequenciamento Completo do Exoma
7.
Semin Thorac Cardiovasc Surg ; 32(4): 947-957, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32621963

RESUMO

Children with Down syndrome (DS) have lower mortality compared to nonsyndromic (NS) children after atrioventricular septal defect (AVSD) repair. Limited data exist regarding hospital mortality and utilization after other congenital heart disease (CHD) operations in DS. We compared hospital mortality and utilization after CHD operations in both populations and hypothesized that the survival benefit in children with DS is not consistent across CHD lesions. The Texas Inpatient Public Use Datafile was queried for all patients <18 years old undergoing operations for CHD between 1999 and 2016. Hospital mortality, length-of-stay and charges were compared between DS and NS groups, stratified by CHD operation using mixed-effects multivariable analyses and propensity score matching analyses adjusting for prematurity, low birth weight, age, and sex. Over the 18-year period, 2841 cases with DS underwent CHD operations compared to 25,063 NS cases. The most common types of interventions performed in DS were AVSD repair, isolated ventricular septal defect (VSD) repair and tetralogy of Fallot (TOF) repair. By multivariable analyses, DS was associated with lower mortality after isolated AVSD repair (RR 0.40 [IQR 0.20-0.79]), and higher hospital mortality after bidirectional Glenn anastomosis (BDG) (RR 5.17 [IQR 2.10-12.77]) and TOF/pulmonary atresia repair (RR 9.71 [IQR 2.16-43.68]) compared to NS children. Similar results were noted using propensity score matching. Children with DS had lower mortality after AVSD repair than NS children, but higher mortality after operations for BDG and TOF/pulmonary atresia. Further study is needed to determine if the presence of pulmonary hypertension in DS modifies the association between DS and mortality depending on cardiac lesion.

8.
Genomics ; 112(5): 2937-2941, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32387503

RESUMO

To further assess the scale and level of parental somatic mosaicism, we queried the CMA database at Baylor Genetics. We selected 50 unrelated families where clinically relevant apparent de novo CNV-deletions were found in the affected probands. Parental blood samples screening using deletion junction-specific PCR revealed four parents with somatic mosaicism. Droplet digital PCR (ddPCR), qPCR, and amplicon-based next-generation sequencing (NGS) were applied to validate these findings. Using ddPCR levels of mosaicism ranged from undetectable to 18.5%. Amplicon-based NGS and qPCR for the father with undetectable mosaicism was able to detect mosaicism at 0.39%. In one mother, ddPCR analysis revealed 15.6%, 10.6%, 8.2%, and undetectable levels of mosaicism in her blood, buccal cells, saliva, and urine samples, respectively. Our data suggest that more sensitive and precise methods, e.g. CNV junction-specific LR-PCR, ddPCR, or qPCR may allow for a more refined assessment of the potential disease recurrence risk for an identified variant.

9.
Am J Med Genet A ; 182(8): 1960-1966, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449285

RESUMO

The mitochondrial aconitase gene (ACO2) encodes an enzyme that catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid cycle. Biallelic variants in ACO2 are purported to cause two distinct disorders: infantile cerebellar-retinal degeneration (ICRD) which is characterized by CNS abnormalities, neurodevelopmental phenotypes, optic atrophy and retinal degeneration; and optic atrophy 9 (OPA9), characterized by isolated ophthalmologic phenotypes including optic atrophy and low vision. However, some doubt remains as to whether biallelic ACO2 variants can cause isolated ophthalmologic phenotypes. A review of the literature revealed five individuals from three families who carry biallelic ACO2 variants whose phenotypes are consistent with OPA9. Here, we describe a brother and sister with OPA9 who are compound heterozygous for novel missense variants in ACO2; c.[487G>T];[1894G>A], p.[(Val163Leu)];[(Val632Met)]. A review of pathogenic ACO2 variants revealed that those associated with OPA9 are distinct from those associated with ICRD. Missense variants associated with either OPA9 or ICRD do not cluster in distinct ACO2 domains, making it difficult to predict the severity of a variant based on position alone. We conclude that biallelic variants in ACO2 can cause the milder OPA9 phenotype, and that the OPA9-related ACO2 variants identified to date are distinct from those that cause ICRD.

10.
Genet Med ; 22(8): 1303-1310, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32336750

RESUMO

PURPOSE: As exome sequencing (ES) is increasingly used as a diagnostic tool, we aimed to compare ES with status quo genetic diagnostic workup for infants with suspected genetic disorders in terms of identifying diagnoses, survival, and cost of care. METHODS: We studied newborns and infants admitted to intensive care with a suspected genetic etiology within the first year of life at a US quaternary-referral children's hospital over 5 years. In this propensity-matched cohort study using electronic medical record data, we compared patients who received ES as part of a diagnostic workup (ES cohort, n = 368) with clinically similar patients who did not receive ES (No-ES cohort, n = 368). RESULTS: Diagnostic yield (27.4% ES, 25.8% No-ES; p = 0.62) and 1-year survival (80.2% ES, 84.8% No-ES; p = 0.10) were no different between cohorts. ES cohort patients had higher cost of admission, diagnostic investigation, and genetic testing (all p < 0.01). CONCLUSION: ES did not differ from status quo genetic testing collectively in terms of diagnostic yield or patient survival; however, it had high yield as a single test, led to complementary classes of diagnoses, and was associated with higher costs. Further work is needed to define the most efficient use of diagnostic ES for critically ill newborns and infants.

11.
Am J Med Genet A ; 182(6): 1387-1399, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32233023

RESUMO

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

12.
Am J Med Genet C Semin Med Genet ; 184(1): 107-115, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31909881

RESUMO

Congenital heart disease (CHD) is the common birth defect worldwide. Despite its recognized burden on public health, the etiology in the vast majority of individuals remains unknown. Chromosomal abnormality plays an important role, frequently observed as large cytogenetically visible rearrangement or small submicroscopic structural variation in the genome. Several genomic disorders are now recognized that are increasingly responsible for CHD with variable penetrance. Single gene disorders, epigenetic alterations, and environmental etiologies are also significant contributors. Our understanding of the genetic basis of CHD has increased exponentially with the escalating use of next generation sequencing to identify ever so small submicroscopic genomic imbalances at the level of coding exons in CHD. This review focuses on genomic disorders other than 22q11.2 deletion, that are major players in the etiology of human cardiac malformations.

13.
Eur J Hum Genet ; 28(5): 674-678, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804630

RESUMO

We report here a de novo missense variant in HIST1H4J resulting in a complex syndrome combining growth delay, microcephaly and intellectual disability. Trio whole exome sequencing (WES) revealed that the proband was heterozygous for a de novo c.274 A > G p.(K91E) variant in HIST1H4J, a gene not yet associated with human disease. The patient presented with profound intellectual disability, microcephaly, and dysmorphic facial features. Functional consequences of the identified de novo missense variant were evaluated in zebrafish embryos, where they affected general development, especially resulting in defective head organs and reduced body axis length. Our results show that the monoallelic p.K91E substitution on HIST1H4J underlies a human syndrome that is genetically and phenotypically akin to the HIST1H4C-associated neurodevelopmental disorder resulting from p.K91A and p.K91Q substitions in HIST1H4C. The highly overlapping patient phenotypes highlight functional similarities between HIST1H4J and HIST1H4C perturbations, establishing the singular importance of K91 across histone H4 genes for vertebrate development.

16.
Sci Adv ; 5(9): eaax2166, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31579823

RESUMO

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Variação Genética , Neurogênese/genética , Proteínas de Ligação a RNA/genética , Transmissão Sináptica/genética , Adolescente , Animais , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Masculino , Camundongos , Neurônios/metabolismo , Linhagem , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Sinapses/genética , Sinapses/metabolismo , Adulto Jovem
17.
Am J Med Genet A ; 179(12): 2459-2468, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520464

RESUMO

Hartnup disease is an autosomal recessive condition characterized by neutral aminoaciduria and behavioral problems. It is caused by a loss of B0 AT1, a neutral amino acid transporter in the kidney and intestine. CLTRN encodes the protein collectrin that functions in the transportation and activation of B0 AT1 in the renal apical brush bordered epithelium. Collectrin deficient mice have severe aminoaciduria. However, the phenotype associated with collectrin deficiency in humans has not been reported. Here we report two patients, an 11-year-old male who is hemizygous for a small, interstitial deletion on Xp22.2 that encompasses CLTRN and a 22-year-old male with a deletion spanning exons 1 to 3 of CLTRN. Both of them present with neuropsychiatric phenotypes including autistic features, anxiety, depression, compulsions, and motor tics, as well as neutral aminoaciduria leading to a clinical diagnosis of Hartnup disease and treatment with niacin supplementation. Plasma amino acids were normal in both patients. One patient had low 5-hydroxyindoleacetic acid levels, a serotoninergic metabolite. We explored the expression of collectrin in the murine brain and found it to be particularly abundant in the hippocampus, brainstem, and cerebellum. We propose that collectrin deficiency in humans can be associated with aminoaciduria and a clinical picture similar to that seen in Hartnup disease. Further studies are needed to explore the role of collectrin deficiency in the neurological phenotypes.


Assuntos
Deleção de Genes , Doença de Hartnup/diagnóstico , Doença de Hartnup/genética , Mutação com Perda de Função , Glicoproteínas de Membrana/genética , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Fenótipo , Alelos , Substituição de Aminoácidos , Animais , Criança , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Adulto Jovem
18.
Am J Hum Genet ; 105(3): 493-508, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447100

RESUMO

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.


Assuntos
Senescência Celular/fisiologia , Histonas/fisiologia , Aneuploidia , Nucléolo Celular/metabolismo , Criança , Cromatina/metabolismo , Metilação de DNA , Feminino , Histonas/química , Humanos , Lactente , Masculino , Pessoa de Meia-Idade
19.
Neurol Genet ; 5(2): e565, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31192300

RESUMO

Objective: To expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene-related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment. Methods: Whole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays. Results: Common clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals. Conclusions: Our results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

20.
Am J Med Genet A ; 179(7): 1376-1382, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31069960

RESUMO

The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.


Assuntos
Haploinsuficiência , Proteínas de Membrana/genética , Fenótipo , Fatores de Transcrição/genética , Sequência de Aminoácidos , Feminino , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana/química , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/química
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