Molecular Syndromology最新文献

Introduction: Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue. We present a rare familial case of two siblings with Nicolaides-Baraitser syndrome (NCBRS) complicated by an initial diagnosis of syndromic craniosynostosis in one of the patients.

Case presentation: Whole exome sequencing (WES) was performed for the affected siblings using the Agilent SureSelect kit and Illumina HiSeq 2500 system, followed by GATK variant calling and in-house annotation. Sanger sequencing was used to validate candidate variants in all immediate family members. A pathogenic de novo variant in TCF12 (p.Gln646Ter), consistent with craniosynostosis type 3 (CRS3), was identified in the proband, along with a novel likely pathogenic variant in SMARCA2 (p.Ile833Phe) involved in NCBRS. The latter was also detected in the sister and is thus suspected to have arisen through germline mosaicism. Various overlapping phenotypic manifestations complicated clinical diagnosis.

Conclusion: This case expands the molecular and clinical spectrum of NCBRS and CRS3 and underscores the utility of trio-based WES in detecting blended phenotypes of disorders with growing phenotypic spectrums. Paternal germline mosaicism may underlie high recurrence and inform reproductive counseling.

Background: Galactosialidosis (GS) is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the CTSA gene. The resulting deficiency of protective protein/cathepsin A leads to reduced β-galactosidase and α-neuraminidase activity, causing multisystem involvement. While typical features include dysmorphic facies, organomegaly, skeletal dysplasia, and neurological impairment, dermatologic manifestations remain poorly characterized.

Case presentation: We report a 9-month-old girl presenting with hepatosplenomegaly and diffuse dermal melanocytosis. Her history included nonimmune hydrops fetalis, congenital cataract, developmental delay, and recurrent respiratory infections. Clinical and radiological evaluation revealed coarse facial features, dysostosis multiplex, and periventricular white matter changes. Enzyme assay demonstrated markedly reduced β-galactosidase activity. Genetic testing identified a homozygous CTSA c.359T>C (p.Ile120Thr) variant, classified as likely pathogenic. Family screening revealed her 10-year-old brother carried the same variant in homozygosity. He exhibited milder features, including developmental delay, hearing loss, and skeletal abnormalities without cutaneous involvement or organomegaly. Enzymatic deficiency was confirmed in both siblings.

Conclusion: This report highlights diffuse dermal melanocytosis as a possible novel cutaneous marker of GS, potentially aiding early recognition. It also illustrates intrafamilial phenotypic variability despite identical genotypes. Our findings underscore the importance of dermatologic clues in the diagnostic workup of lysosomal storage disorders and advocate for family-based genetic screening to identify asymptomatic or mildly affected individuals.

Background: Hyperphenylalaninemia (HPA, increased blood phenylalanine levels) refers to a disorder spectrum, with phenylketonuria (PKU) being the most common, caused by PAH gene variants in an autosomal recessive inheritance form. Genetic differences significantly influence phenotypical outcomes in HPA patients. This study investigates the genotype-phenotype correlation of HPA patients, aiming to evaluate treatment consistency based on specific genotypes and demonstrate that genotyping can provide guidance for optimal treatment.

Methods: Genomic DNA was obtained from 50 PKU, 2 tetrahydrobiopterin (BH4) deficiency, and 1 dihydropteridin reductase deficiency patients for next-generation sequencing of HPA-associated genes. Variants were analyzed using the Sophia DDM program, dbSNP, ClinVar, Ensembl information services, and ACMG 2015 criteria. Allelic phenotypical values consistent with enzyme functionality based on literature data were assessed using anamnesis information.

Results: Carriers of two null variants (homozygous/compound heterozygous) were unresponsive to BH4 therapy, reflecting the existing literature. Notably, BH4 therapy was also inadequate for two PKU patients who were compound heterozygous carriers with one null variant (P3, P10), even with other variants assumed protein function (PAH [NM_000277.3] c.1289T>C, c.143T>C). However, PAH variants c.1169A>G (P21) and c.898G>T (P25) demonstrated positive BH4 responses when compounding a null variant, along with a c.782G>A homozygous patient benefiting from BH4. Two novel variants were observed in PTS and QDPR genes, respectively.

Conclusion: This study implies that genetic testing is plausible in predicting pretreatment BH4 testing outcomes, aiding in decision-making before patient evaluation, and providing valuable guidance to metabolism specialists during HPA treatment. With more HPA genotypes analyzed and clinical data published, genotyping will hold a better deterministic position toward patient prognosis and therapeutic management.

Introduction: Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders. NDDs caused by rare gene mutations are referred to as Rare Genetic Neurodevelopmental Syndromes (RGNS). Witteveen-Kolk syndrome (WITKOS) is such a RGNS, caused by heterozygous mutations in SIN3A and characterized by developmental problems, facial dysmorphisms, short stature, brain abnormalities, intellectual disability, and behavioral problems. Care for individuals with WITKOS mainly focuses on somatic characteristics. To address this issue, we present a case study of the first documented treatment of behavioral problems in WITKOS.

Case presentation: The patient is a 27-year-old single female with known developmental problems during childhood and a history of severe psychiatric problems. She received the genetically confirmed diagnosis of WITKOS at the age of 25 and based upon extensive intellectual and neuropsychological examination, a personalized psychological treatment could be performed. This treatment consisted of twelve individual sessions aimed to reduce anxiety, fatigue and thought disorder by treating factors contributing to cognitive overload. Evaluation during treatment and at 3-month follow-up showed a positive increase in functioning and acceptance as well as the acceptance of successive follow-up treatment. However, she was unable to maintain favorable changes in emotion-regulation strategies at follow-up, emphasizing the need for prolonged professional guidance and support.

Conclusion: Neurocognitive evaluation enabled the adaptation of treatment strategies to the patients developmental and neurocognitive functioning, provided guidance in treatment choice, supported the rewriting of her personal narrative and resulted in successive care.

Background: HERC2 encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy, and various structural anomalies. This report aimed to expand phenotypic spectrum of HERC2-related disorders, including an unusual cardiac manifestation.

Case presentation: The proband, a male infant born to consanguineous parents, presented with myoclonia-like eyelid movements at 50-days old and subsequently developed severe neuromotor regression and choreoathetotic movements. Brain magnetic resonance imaging revealed diffuse cerebral atrophy, corpus callosum thinning, and bilateral pachygyria. He also exhibited distinct dysmorphic features and dilated cardiomyopathy, confirmed by echocardiography. His sibling presented with similar features, including severe developmental delay and dilated cardiomyopathy. Whole-exome sequencing identified a homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the HERC2 gene. This case report is significant as it describes dilated cardiomyopathy in MRT38, a manifestation not previously associated with HERC2 variants. The unusual cardiac phenotype suggests a potential link between HERC2 dysfunction and mitochondrial impairment, contributing to cardiomyopathy.

Conclusion: These patients underscore the importance of recognizing novel clinical features associated with the HERC2 LoF variants, which can guide disease characterization and patient management.

Introduction: Complex hereditary spastic paraplegias (HSPs) are defined by progressive spasticity with diverse neurological manifestations, complicating the diagnostic process. Pathogenic variants in genes encoding subunits of the adaptor protein complex-4 (AP4), including the AP4S1 gene, have been implicated in a subset of HSPs.

Case presentation: We report three siblings with complex HSP harboring pathogenic AP4S1 gene variants, focusing on the clinical characteristics and the diagnostic challenges and pitfalls. The patients exhibited common clinical features such as progressive spasticity, distinctive craniofacial features, and neurodevelopmental delays. Neuroimaging findings included agenesis of the corpus callosum and ventricular enlargement in two siblings, whereas one sibling demonstrated normal brain imaging. Initially, these cases were misdiagnosed as cerebral palsy, leading to unwarranted surgical interventions for tethered cord syndrome. Copy number variation analysis identified homozygous deletions in the AP4S1 gene.

Conclusion: In patients with progressive spasticity, seizures, distinctive craniofacial features, and neuroimaging anomalies, AP4S1-related HSP should be considered in the differential diagnosis. Enhanced awareness and further studies are vital for improving diagnostic precision and management of these intricate neurogenetic disorders.

Introduction: The lamin-B receptor (LBR) gene has two primary functions: maintaining the structural integrity of the nuclear envelope and playing a role in cholesterol biosynthesis. Heterozygous variants in the LBR gene have been associated with Pelger-Huët anomaly (PHA, OMIM #169400), while homozygous or compound heterozygous mutations have been associated with rhizomelic skeletal dysplasia, with or without PHA (OMIM #618019) and Greenberg dysplasia (OMIM #215140).

Case presentation: We report a 4-year-old boy presenting with short stature and short limbs and his mother exhibiting milder findings. Genetic analysis revealed a heterozygous c.1640A>G (p.Asn547Ser) and c.43C>T (p.Arg15*) variants in the LBR gene in both the boy and his mother. The father was identified as a heterozygous carrier of the c.43C>T (p.Arg15*) variant. Peripheral blood smears confirmed the PHA in the patient and his parents.

Conclusion: The phenotypic differences observed between the mother and male child in our study highlight the genetic variability and regressive nature of LBR-related skeletal dysplasias. This report shows the complexity of LBR-related phenotypes and expands the clinical spectrum of LBR mutations in rhizomelic skeletal dysplasia with PHA.

Background: Joubert syndrome type 33 (JBTS33) is a rare autosomal recessive disorder characterized by developmental delay, severe renal disease, hypotonia/ataxia, cerebellar vermian hypoplasia/aplasia, optic nerve atrophy, renal atrophy, and the "molar tooth sign" on imaging. Nearly 40 genes associated with Joubert syndrome have been identified, including CEP290, TMEM216, TMEM67, AHI1, and CC2D2A.

Methods: We report a consanguineous family with JBTS33 diagnosed through whole-exome sequencing. A novel biallelic homozygous nonsense mutation (ENST00000326291.11: c.1231C>T; p.Arg411Ter) in progesterone-induced blocking factor 1 (PIBF1) was identified.

Results: Our study included 3 patients with the same homozygous mutation in PIBF1, which contributed to clinical features such as psychomotor issues, dysmorphic features, hypotonia/ataxia, kidney failure, and possibly seizures. All 3 patient seizures have been eliminated after phenobarbital administration. This mutation has not been reported in public databases.

Conclusion: This study confirmed PIBF1 as a disease-causing gene for JBTS33, expanding the molecular and clinical spectrum of JBTS. Our findings underscore the importance of identifying the genetic underpinnings and phenotypic expansions of PIBF1 mutations. Enhanced diagnostic awareness can facilitate early intervention and management. Further research is required to elucidate the relationship between PIBF1 mutations and associated clinical manifestations.

Introduction: Cornelia de Lange syndrome is a rare congenital malformation syndrome characterized by prenatal-onset growth retardation, with typical facial findings that include bushy eyebrows, synophrys, long and thick eyelashes, ptosis, anteverted nostrils, long philtrum, and thin and downward sloping vermilion. The syndrome is caused by mutations in NIPBL, SMC1A, SMC3, RAD21, HDAC8, and ANKRD11 genes encoding cohesin complex proteins that maintain a chromatin structure in cell proliferation. In recently reported cases, new genes that are not involved in the cohesin complex but clinically cause CdLS have been identified. With these newly identified genes, the term chromatinopathies has been offered for this syndrome as it is more inclusive. Patients with the syndrome are classified as classical CdLS or CdLS-like phenotype according to their clinical features.

Methods: The clinical and molecular results of 17 new cases of CdLS are reported.

Results: The patients, who were between 2 months and 12 years of age, all had unique facial findings as well as growth retardation. Congenital malformations accompanying the syndrome in the patients were different. The molecular analysis showed genetic etiology in 13 patients, of which 2 were deletions and 11 were pathogenic missense variants in the NIPBL, HDAC8, and SMC1A genes and of these variants, some had not been reported previously.

Conclusion: By presenting the clinical and molecular results of these CdLS cases, it was aimed to expand the clinical spectrum, contribute to a better understanding of the genotype-phenotype relationship, and highlight the importance of molecular methods used in the diagnosis of genetic diseases.

Introduction: Chromosomal microarray analysis (CMA) allows the detection of submicroscopic chromosomal abnormalities such as unbalanced translocations and inversions. In recent years, its use in prenatal diagnosis has been implemented when certain ultrasound findings are detected. The purpose of this study was to analyze and describe the imbalances detected in prenatal samples collected from pregnancies followed in our center for having the indication to perform diagnosis using CMA.

Material and method: On a population of pregnant women of 13,685, 216 CMAs were performed on chorionic villi and amniotic fluids during the period 2019-2023. The inclusion criteria were normal screening of common aneuploidies and at least one of the following features: nuchal translucency higher than percentile 99, fetal abnormalities, early-onset fetal growth restriction, parents' history of chromosomal imbalances, or cases with chromosomal imbalances. When a relevant variant was detected, it was analyzed in the parents' fetus and when available, the phenotype of the born children was collected.

Results: Pathogenic copy number variations (CNVs) were detected in 13 of 216 samples (6%). In a single sample, two concurrent CNVs were detected. Isolated CNVs had OMIM numbers and corresponded to already reported syndromes. Seven variants of unknown significance (3.7%) were observed. The study of the parents showed that 14 of 21 variants identified had arisen de novo (one pathogenic and five unknown CNVs had been inherited from an apparently healthy parent). Three microduplications specially drew our attention: duplication 5q35.2 which encompassed MSX2 gene (because the reported phenotype is not consistent with what is expected for the genomic region) and duplications 1q21.1 and 16p11.2 (due to the ultrasound findings detected in fetuses had recently been postulated to be associated with these CNVs).

Conclusion: The phenotype of CNVs identified in prenatal samples is highly variable prenatally, like postnatally. Some findings may be part of the syndromes to which they give rise and some phenotypes may be pending to define. Further studies are needed to better define these variants and to understand how haploinsufficiency or over-expression of genes included in these regions can cause such complex phenotypes.