Molecular Syndromology

INTRODUCTION: Cornelia de Lange syndrome (CdLS) is a rare congenital malformation characterized by distinctive facial features, short stature, and limb defects. In addition, half of the patients with CdLS exhibit repetitive self-injurious behaviors (SIBs) related to intellectual disability with autistic traits. CdLS is caused by pathogenic variants of genes encoding the cohesin complex pathway, with 70% of these variants identified in the nipped-B-like ( NIPBL ) gene. CASE PRESENTATION: We report 2 patients with CdLS who exhibited repetitive SIBs...

INTRODUCTION: FBLN5 -related cutis laxa is a very rare, autosomal recessive syndrome that is characterized by loose, wrinkled, and redundant skin, sagging cheeks, emphysema, aortic or pulmonary artery abnormalities, inguinal hernia, and diverticula of the gastrointestinal and urinary tract. CASE PRESENTATION: In this study, we report an 8-year-old Turkish girl with a novel homozygous missense variant in the FBLN5 gene, c.862G>T, p.(Asp288Tyr). Her unaffected parents were carriers of the same variant...

INTRODUCTION: HNF1B -associated diseases are a group of genetic conditions that affect the kidney as well as other organ systems. Kidney anomalies are the most common symptoms. Other defects may include early-onset diabetes, genital abnormalities, and abnormalities of pancreas and liver function. Renal involvement has emerged as the earliest finding in HNF1B disease, even in prenatal life, with the most common feature being hyperechogenic kidneys. CASE PRESENTATION: In this study, we present 3 fetuses with bilateral renal hyperechogenicity identified by ultrasound in the second trimester...

INTRODUCTION: Congenital heart disease (CHD) is the most common type of congenital defect reported to be one of the leading causes of mortality in the first year of life. Microdeletion and microduplication syndromes (MMS) are associated with cardiac malformations. Understanding which genetic factors are involved in these conditions directly impacts treatment decisions. We aimed to identify the occurrence of genetic alterations and their association with MMS in CHD pediatric patients evaluated in a reference service of Southern Brazil...

INTRODUCTION: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. METHODS: In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature...

BACKGROUND: Prolonged exposure to glucocorticoids can result in the development of Cushing's syndrome. Excess serum cortisol can occur due to several factors including exogenous steroids, pituitary and adrenal adenoma, and ectopic ACTH secretion. SUMMARY: The last 2 decades have seen significant progress in identifying new genetic and molecular mechanisms underlying hypercortisolemia. This has implicated mutations seen in a multitude of aberrant pathways that underpin the pathophysiology of Cushing's syndrome...

INTRODUCTION: Cri-du-chat syndrome is generally diagnosed when patients present a high-pitched cry at birth, microcephaly, ocular hypertelorism, and prominent nasal bridge. The karyotype is useful to confirm deletions in the short arm of chromosome 5 (5p-) greater than 10 Mb. In cases of smaller deletions, it is necessary to resort to other molecular techniques such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA) or genomic array. CASE PRESENTATION: We report a family with an atypical deletion in 5p (mother and 2 children) and variable phenotypes compared with the literature...

INTRODUCTION: Mendelian disorders of the epigenetic machinery are a growing group of disorders exhibiting several overlapping clinical features that are probably due to common abnormalities at the epigenomic level, which lead to downstream convergence at the transcriptomic level. CASE PRESENTATION: Here, we report a new case of short stature, brachydactyly, intellectual developmental disability, and seizures (SBIDDS) syndrome with a severe ocular phenotype and hypogonadism...

INTRODUCTION: 3M syndrome is an autosomal recessive disorder characterized by characteristic facial features, severe pre- and postnatal growth restriction (<-4 SDS), and normal mental development. 3M syndrome is genetically heterogeneous. Up to date, causative mutations have been demonstrated in 3 genes, cullin-7 ( CUL7 ), obscurin-like 1 ( OBSL1 ), and coiled coil domain containing protein 8 ( CCDC8 ). CASE PRESENTATION: Here, we report a patient who was referred to our clinic due to short stature and developmental delay...

INTRODUCTION: Whole-exome sequencing (WES) is becoming widely available in prenatal diagnosis. However, as with most scientific methods, WES also has its limitations. The aim of the study was to report a fetal case of RNU4ATAC -opathy which was missed by prenatal WES. CASE PRESENTATION: A 28-year-old healthy primigravida was revealed by ultrasound at 20 + 3 weeks of gestation to have a fetus with ventriculomegaly (left 15.1 mm/right 11.9 mm), hypoplastic vermis, and mild growth retardation...

INTRODUCTION: Pathogenic variants in the SLC26A2/DTDST gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of SLC26A2/DTDST -related disorders. METHODS: The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS)...

INTRODUCTION: Copy-number variations (CNVs) impacting on small DNA stretches and associated with language deficits provide a unique window to the role played by specific genes in language function. METHODS: We report in detail on the cognitive, language, and genetic features of a girl bearing a small deletion (0.186 Mb) in the 2p16.3 region, arr[hg19] 2p16.3(50761778_50947729)×1, affecting exons 3-7 of NRXN1 , a neurexin-coding gene previously related to schizophrenia, autism (ASD), attention deficit hyperactivity disorder (ADHD), mood disorder, and intellectual disability (ID)...

INTRODUCTION: Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is a rare disease with an early onset and severe phenotype. The pathogenic mechanism associated with mutations in the gene COL7A1 has been widely studied and many related cases have been reported, but prenatal cases are rare. Here, we report the prenatal diagnosis of a sporadic case of RDEB. METHODS: In this study, the fetus with abnormal skin manifestations, which were determined during a prenatal ultrasound, was evaluated based on the ultrasound and autopsy findings and the results of molecular diagnostic analyses...

INTRODUCTION: Calcium/calmodulin-dependent serine protein kinase ( CASK ) gene mutations cause microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability. Congenital heart disease (CHD) is a rare complication reported in only 4 male patients with full loss-of-function mutations. Here, we report the first male patient with mosaicism of a truncating variant of CASK complicated by CHD. CASE PRESENTATION: The patient is a 6-year-old male with MICPCH, ventricular septal defect, and developmental delay...

INTRODUCTION: Autosomal dominant pathogenic variations in the CSNK2A1 gene cause Okur-Chung neurodevelopmental syndrome (OCNDS). METHODS: The proband and her parents were examined thoroughly and observed for any issues related to OCNDS. Furthermore, peripheral blood samples were collected from each subject for further investigations. Whole-exome sequencing identified a pathogenic variant in CSNK2A1 (NM_001895: c.62G>A, p.R21Q; rs1402734448). RESULTS: The proband has global developmental delay, speech disorders, epilepsy, and behavioral issues...

INTRODUCTION: Vein of Galen malformation (VGM) results from an aneurysmal aberration with an arteriovenous shunting of blood and is the most frequent arteriovenous malformation in infants and fetuses. The congenital malformation develops during weeks 6-11 of fetal development. Infants often die from high-output congestive heart failure. VGM is mostly considered as a sporadic condition with minimal recurrence risk in subsequent pregnancies. Mendelian forms of VGM have rarely been described as infrequent phenotypic presentations of 2 disorders: capillary malformation-arteriovenous malformation syndrome ( RASA1 , EPHB4 ) and hereditary hemorrhagic telangiectasia ( ENG , ACVRL1 , and SMAD4 ), both showing autosomal dominant inheritance...

INTRODUCTION: Mosaic variegated aneuploidy syndrome 2 (MVA2) and Noonan syndrome (NS) are 2 genetic disorders with overlapping clinical features, including intrauterine growth retardation, dysmorphic features, and heart defects. Whereas NS is a well-known congenital entity, MVA2 is rare, and only a few cases have been reported in the literature. CASE PRESENTATION: We report on the molecular findings in 3 patients with short stature phenotypes from the same family...

INTRODUCTION: Transient infantile hypertriglyceridemia (HTGTI) is a rare autosomal recessive disease. At present, only 20 cases of HTGTI have been reported worldwide. Hence, it is necessary to further assess the phenotypic and genetic variation spectra of HTGTI. CASE PRESENTATION: A 10-month-old male infant was diagnosed with hypertriglyceridemia, hepatomegaly, liver injury, fasting hypoglycemia, and insulin resistance. Trio-whole exome sequencing (trio-WES) was performed on the patient and his parents...

INTRODUCTION: Heterozygous loss-of-function variants in the last 2 exons of KIDINS220 have been associated with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO). Syndromic features of this condition include macrocephaly and dilatation of the lateral ventricles. Homozygous variants in the more proximal exons of KIDINS220 have been reported in several fetuses with a similar but more severe phenotype of limb contractures and severe ventriculomegaly identified in the second trimester of pregnancy...

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