BACKGROUND: Monocarboxylate transporter 8 (MCT8) deficiency, also known as Allan-Herndon-Dudley syndrome, is a rare X-linked genetic disorder resulting from pathogenic mutations in the gene. MCT8 deficiency impacts the...BACKGROUND: Monocarboxylate transporter 8 (MCT8) deficiency, also known as Allan-Herndon-Dudley syndrome, is a rare X-linked genetic disorder resulting from pathogenic mutations in the gene. MCT8 deficiency impacts the transport of thyroid hormone (TH) throughout the body. Symptoms are highly heterogeneous and often include severe neurodevelopmental delay, hypotonia in the limbs and trunk, and low body weight. CASE PRESENTATION: This case report describes the diagnostic journey of two brothers born 1 year and 8 months apart to nonconsanguineous parents. Both exhibited severely limited motor development, quadriparesis, and an inability to sit independently or hold their head up. Despite their significant clinical presentations, the diagnoses were delayed: 12 years and 8 months for Case 1 and 8 years and 3 months for Case 2. Genetic testing revealed that both patients carry the same novel mutation, 960_995del (p.Tyr321_Ala332del). Although they displayed key clinical features of MCT8 deficiency, the TH profile of Case 1 was inconclusive, lacking the characteristic sustained elevation of triiodothyronine (T3) typically associated with MCT8 deficiency. CONCLUSIONS: Findings from this case report highlight the need for greater awareness of this disorder and underscore the clinical heterogeneity of MCT8 deficiency.
Diaphragmatic rupture is an uncommonly seen complication of classical Ehlers-Danlos syndrome (cEDS). There have been no documented cases of diaphragmatic hernia in newborns having cEDS. This case study discusses a male i...Diaphragmatic rupture is an uncommonly seen complication of classical Ehlers-Danlos syndrome (cEDS). There have been no documented cases of diaphragmatic hernia in newborns having cEDS. This case study discusses a male infant delivered through spontaneous vertex delivery to a mother with cEDS. No evidence of a diaphragmatic hernia was found 6 days before delivery when an ultrasound scan to monitor a ventricular septal defect was carried out. Postnatally, the infant displayed signs of severe respiratory distress. A chest radiograph revealed a diaphragmatic hernia. The surgical team found and corrected a small posterolateral diaphragmatic defect on the third day of life. This resulted in a good recovery following management of a complication of chylothorax. The mother was known to have cEDS and bidirectional sequencing of the patient's lymphocyte DNA detected the heterozygous pathogenic familial variant c.934C > T;p.(Arg312Cys). This variant has been previously reported in cases of cEDS. Other variants are known to be associated with arthrochalasia-type EDS and osteogenesis imperfecta, but no variants have been associated previously with congenital diaphragmatic hernia or diaphragmatic rupture. The familial variant impacts the highly conserved arginine residue in the Gly-X-Y triplet motif of the Type-I collagen protein. It has been reported in various families as a rare cause of autosomal-dominant cEDS. This case report details the patient's journey, including images of radiographs, highlighting a rare but important complication of spontaneous vertex delivery for individuals with cEDS. We also include a literature review on diaphragmatic hernia and rupture in classical EDS.
Primary ciliary dyskinesia (PCD) is a rare, inherited disease resulting from abnormal structure and/or function of cilia. To date, pathogenic variants in over 50 genes have been reported as causes of PCD. One of the gene...Primary ciliary dyskinesia (PCD) is a rare, inherited disease resulting from abnormal structure and/or function of cilia. To date, pathogenic variants in over 50 genes have been reported as causes of PCD. One of the genes, , presents a diagnostic challenge due to the existence of , a highly homologous pseudogene that significantly complicates accurate molecular diagnosis. Here, we present a 43-year-old female with a clinical diagnosis of PCD seeking molecular diagnosis underlying her disease. Short-read genome sequencing detected two potentially pathogenic variants (c.5416C > T and c.3786-1G > T), but clinical validation was hindered due to the pseudogene overlap. Using clinical long-read genome sequencing (lrGS), we confirmed the presence of both pathogenic variants and a configuration, establishing the molecular diagnosis for this patient. This case highlights the promise of lrGS in diagnosing -related PCD and demonstrates that offering lrGS to PCD patients, especially those with suspected variants, could enhance diagnostics, disease management, and genetic counseling.
Parkinson's disease (PD) is a neurodegenerative condition characterized by progressive loss of dopaminergic neurons and by heterogeneous etiologies and clinical manifestations. Juvenile-onset forms are rare and can be ca...Parkinson's disease (PD) is a neurodegenerative condition characterized by progressive loss of dopaminergic neurons and by heterogeneous etiologies and clinical manifestations. Juvenile-onset forms are rare and can be caused by biallelic mutations in several genes. Kufor-Rakeb syndrome (KRS) is an autosomal-recessive form of early-onset parkinsonism caused by pathogenic variants in the () gene. This P5B-ATPase dysfunction impairs lysosomal processing, leading to the accumulation of -synuclein. Here, we present the first documented Guatemalan case of KRS, a young woman with progressive motor and cognitive decline. Genetic testing identified a homozygous pathogenic variant in . This report underscores the importance of recognizing KRS in diverse populations and of using gene-based testing to guide diagnosis, counseling, and multidisciplinary supportive care.
Juvenile polyposis syndrome (JPS) (MIM: 174900) is a rare genetic disorder characterized by multiple benign, hamartomatous polyps, and an increased risk for colorectal and gastric cancer. It is caused by pathogenic varia...Juvenile polyposis syndrome (JPS) (MIM: 174900) is a rare genetic disorder characterized by multiple benign, hamartomatous polyps, and an increased risk for colorectal and gastric cancer. It is caused by pathogenic variants in and . We present the findings of a mosaic pathogenic variant in a 57-year-old patient with newly diagnosed colon cancer and a history of polyps, which were later discovered to be JPS polyps. The variant was first identified in a blood sample at approximately 15% allele frequency. Subsequent genetic testing performed on gDNA from cultured fibroblasts found this variant to be present at very low levels (< 10%). The finding of this variant in two sample types, as well as the history of JPS polyps, supports a diagnosis of JPS due to a mosaic pathogenic variant. This diagnosis affects cancer screening recommendations for our patient and his relatives. Our case highlights the need for recognition and workup of potentially mosaic cases and for universal germline genetic testing for patients with colorectal cancer.
The gene encodes the steroid 5α-reductase-2 isozyme, which converts testosterone to dihydrotestosterone and plays a key role in sexual development and androgen physiology. Deficiency of this enzyme leads to an autosomal...The gene encodes the steroid 5α-reductase-2 isozyme, which converts testosterone to dihydrotestosterone and plays a key role in sexual development and androgen physiology. Deficiency of this enzyme leads to an autosomal recessive sex-linked disorder associated with ambiguous genitalia and hypovirilization/complete feminization of external genitalia in individuals with a 46,XY karyotype. The present study emphasizes the indispensable role of molecular genetic testing in siblings (Probands 1 and 2) presented with disorders of sexual development (DSD). The biochemical, cytogenetics, and molecular testing, encompassing hormonal testing, chromosomal analysis, fluorescence in situ hybridization (FISH), and whole exome sequencing (WES), were carried out at our National Reference Laboratory. In addition, Sanger sequencing confirmed the identified variant, and bioinformatics tools were used to assess its impact on protein structure and stability, thereby assessing its pathogenic potential. The biochemical profile revealed highly elevated testosterone/dihydrotestosterone in Probands 1 and 2 as 45.4 and 43.2, respectively (biological reference range < 10). The cytogenetic analysis confirmed a 46,XY karyotype, and FISH validated the presence of the gene. WES identified a pathogenic homozygous variant, c.737G > A(p.Arg246Gln) in the gene. Protein structure predictions and stability analyses indicated the variant's damaging effects. This study supports diagnosis through comprehensive molecular testing and highlights the significance of genetic insights in managing 46,XY DSD. This case highlights phenotypic variability in siblings with the same homozygous variant from a nonconsanguineous Indian family, underscoring the need for early genetic workup and multidisciplinary evaluation in 46,XY DSD.
Buratti-Harel syndrome (BURHAS) is a rare genetic condition caused by heterozygous pathogenic variants of the gene, with only five unrelated cases included in a single report in 2019. BURHAS is characterized mainly by n...Buratti-Harel syndrome (BURHAS) is a rare genetic condition caused by heterozygous pathogenic variants of the gene, with only five unrelated cases included in a single report in 2019. BURHAS is characterized mainly by neurodevelopmental delay, infantile hypotonia, and dysmorphic features. We report the case of a 9-year-old Chilean female that matches this phenotype, with a heterozygous, frameshift variant of the gene.
Biallelic pathogenic variants in cause a form of congenital myasthenic syndrome (CMS), which is typically characterized by fatiguable muscle weakness, hypotonia, and feeding difficulties that present in the neonatal per...Biallelic pathogenic variants in cause a form of congenital myasthenic syndrome (CMS), which is typically characterized by fatiguable muscle weakness, hypotonia, and feeding difficulties that present in the neonatal period or early childhood. -associated CMS can be treated with acetylcholinesterase inhibitors. Here, we present a 4-year-old male with a history of neonatal respiratory distress, hypotonia, and muscle weakness exacerbated by illness who underwent trio genome sequencing and was found to have biallelic single nucleotide variants at the same position in , encoding NM_005055.5:c.264C > A p.(N88K) and NM_005055.5:c.264C > G p.(N88K). The paternally inherited c.264C > G variant has not been previously reported. Interestingly, only the maternally inherited c.264C > A variant was reported on the patient's prior clinical exome sequencing, which delayed diagnosis and initiation of treatment for this patient. This case highlights the complexity of identifying multiallelic variants during exome and genome sequencing analysis. Additionally, this case is the first report of facial malformations in a patient with -associated CMS due to variants outside of the promoter region. ClinicalTrials.gov identifier: NCT02450851.
Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by short telomeres. We report two patients that presented with bone marrow failure (BMF), who were identified to have low telomere length...Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by short telomeres. We report two patients that presented with bone marrow failure (BMF), who were identified to have low telomere length (TL) and variants of uncertain significance (VUS) in two different telomere genes inherited from their parents. At age 6, Patient 1 had stage 4 neuroblastoma. He was treated with chemotherapy, surgery, immunotherapy, and autologous stem cell rescue. At age 10, he developed pancytopenia. Bone marrow biopsy revealed hypocellular marrow and der (1; 7), associated with myelodysplastic syndrome. Germline genetic evaluation showed a pathogenic variant in DNAJC21 (from father) and VUS in NAF1 (c.1375C > T) (from father) and RTEL1 (c.533T > C) (from mother). The patient was found to have very low TL (VLTL) (< 1st percentile) in 4/6 white blood cell subsets. The patient's mother was found to have borderline low TL (VLTL) ( 1 and < 10th percentiles) in 4/6 subsets and VLTL in 1/6 subsets. Father had VLTL in 1/6 but normal TL in other subsets. Neither parent reported any symptoms of TBD. Patient 2 presented with a depressed skull fracture at age 15. He was found incidentally to have pancytopenia. Bone marrow biopsy showed hypocellular marrow and no cytogenetic abnormalities. The patient had VLTL in all 6/6 subsets. Genetic evaluation showed VUSs in TERT (c.3158-80G > A) (from mother), TINF2 (c.814T > C) (from mother) and SRP72 (c.1928C > T) (from father). Mother was also found to have VLTL in all 6 subsets but has reported good health except for premature graying of hair. These two patients presented with BMF, identified to have VUSs in more than one TBD-associated gene with functional evidence of shortened telomeres, highlighting the potential for a digenic mode of inheritance. Synergy between two VUSs could contribute to a penetrant phenotype and resulting in earlier or more severe onset of disease.
We report a 71-year-old female patient with a history of intellectual disabilities, dysmorphic features, schizoaffective disorder, bipolar type, and psychosis. Exome sequencing revealed a novel, heterozygous, predicted l...We report a 71-year-old female patient with a history of intellectual disabilities, dysmorphic features, schizoaffective disorder, bipolar type, and psychosis. Exome sequencing revealed a novel, heterozygous, predicted loss-of-function variant in the gene (NM_015711.3: c.1910del, p.[Leu637ArgfsTer87]). Heterozygous rare variants in have been associated with Coffin-Siris Syndrome 12 (CSS-12; OMIM #619325). This is the oldest patient to date with a pathogenic variant in . This case report expands the clinical phenotype associated with variants and sheds light on the long-term prognosis.
INTRODUCTION: Emanuel syndrome is a rare chromosomal disorder characterized by severe developmental disability and variable clinical manifestations. Although congenital anomalies are relatively common, there is no pathog...INTRODUCTION: Emanuel syndrome is a rare chromosomal disorder characterized by severe developmental disability and variable clinical manifestations. Although congenital anomalies are relatively common, there is no pathognomonic prenatal pattern. In some cases, structural defects are absent or not detectable prenatally, making the potential role of soft ultrasound markers particularly relevant. CASE PRESENTATION: We report a case of Emanuel syndrome in which no structural malformations were identified prenatally. First-trimester ultrasound revealed an isolated increased nuchal translucency of 3.2 mm. Postnatally, the infant exhibited severe hypotonia, dysmorphic features, and profound developmental delay, but no gross structural defects were observed. Cytogenetic and FISH analyses confirmed an additional der(22)t(11; 22) chromosome inherited from the mother. DISCUSSION: A review of the limited literature on first-trimester findings suggests that increased nuchal translucency has been observed in several cases of Emanuel syndrome, although the available data remain insufficient to assess predictive value. Nevertheless, the recurrence of this observation across independent reports indicates that NT enlargement may warrant attention as a potential prenatal marker. CONCLUSION: While current evidence is insufficient to draw definitive conclusions, this case highlights that isolated NT thickening may represent the only prenatal sign of Emanuel syndrome. Evaluation in larger cohorts and future prospective studies will be essential to determine the sensitivity and specificity of this marker for early diagnosis of the syndrome and the timely identification of balanced translocation carriers.
Sickle cell trait (SCT) increases the risk of sudden death and exertional rhabdomyolysis (ER) in athletes and Service Members (SMs) during intense exercise. Exertional injuries in SCT carriers can result in exercise coll...Sickle cell trait (SCT) increases the risk of sudden death and exertional rhabdomyolysis (ER) in athletes and Service Members (SMs) during intense exercise. Exertional injuries in SCT carriers can result in exercise collapse associated with SCT (ECAST), an under-recognized condition characterized by variable clinical presentations ranging from ischemic muscle pain to fulminant collapse. This study presents clinical and genetic findings of two independent Black SMs with history of ECAST triggered by strenuous exercise. ECAST cases carried pathogenic heterozygous mutations : p.Gly848Ser and p.Met282Ile associated with mitochondrial DNA depletion syndromes. Mononuclear cell mitochondria extracted from ECAST cases showed impaired mitochondrial profiles and resilience, demonstrating the potential contribution of mitochondrial dysfunction to exertional collapse in SCT carriers.
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha ()-related overgrowth spectrum (PROS) is a group of rare genetic asymmetric and atypical overgrowth disorder syndromes. Affecting skin, adipose and c...Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha ()-related overgrowth spectrum (PROS) is a group of rare genetic asymmetric and atypical overgrowth disorder syndromes. Affecting skin, adipose and connective tissues, brain, bone, and vasculature and severity influenced by the gestational age at which the change occurred, PROS is phenotypically heterogeneous. This paper shares the case report of a former extremely preterm infant diagnosed with a subtype of PROS, megalencephaly-capillary malformation/megalencephaly-capillary malformation polymicrogyria (MCAP) syndrome, for whom treatment with alpelisib was initiated at 10 months of age (7 months corrected age). To our knowledge, this patient is the third and youngest to be included in this expanded access program for compassionate use for patients under 2 years of age.
Nonimmune hydrops fetalis (NIHF) refers to the pathologic accumulation of fluid within the fetus due to causes other than red cell alloimmunization and now accounts for up to 90% of fetal hydrops cases. Fetal hydrops is...Nonimmune hydrops fetalis (NIHF) refers to the pathologic accumulation of fluid within the fetus due to causes other than red cell alloimmunization and now accounts for up to 90% of fetal hydrops cases. Fetal hydrops is associated with significant morbidity and mortality, and the exact prognosis is largely dependent on the underlying etiology. The most common etiologies include cardiovascular causes and chromosomal or genetic abnormalities. Despite this, diagnostic testing with karyotype or chromosomal microarray only identifies approximately 25% of cases, and up to 20% of cases remain idiopathic or unknown. We report the first known case of NIHF related to a pathogenic variant. In this case, NIHF was diagnosed at 30 weeks' gestation in a fetus with low-risk prenatal genetic screening, noncontributory anatomic survey, and normal chromosomal microarray. The hydrops was uniquely localized to scalp edema and pleural effusions requiring bilateral thoracentesis and never progressed to involve pericardial effusion or ascites. Whole exome sequencing diagnosed a novel pathogenic variant in the gene. This is the first reported case of NIHF in the setting of pathogenic variant and is an important addition to the existing literature on this incredibly diverse, high-risk pathology.
van der Meulen M, van Wezel JT, Terlouw D
… +8 more, Morreau J, Steeghs EMP, van Doorn R, van Leerdam ME, Onnekink AM, de Ruiter MC, van der Stoep N, Potjer TP
is the primary high-risk predisposition gene for familial cutaneous melanoma. In the Netherlands, most carriers of pathogenic germline variants in harbor a unique, population-specific founder variant, c.225_243del, comm...is the primary high-risk predisposition gene for familial cutaneous melanoma. In the Netherlands, most carriers of pathogenic germline variants in harbor a unique, population-specific founder variant, c.225_243del, commonly referred to as p16-. For decades, this distinctive 19 base-pair deletion in had been identified exclusively as a germline variant. Here, we report an exceptional case of somatic mosaicism for the p16- variant in an Irish male with a concurrent diagnosis of Kartagener's syndrome but no history of malignancy. The variant was first identified through targeted next-generation sequencing (NGS) of a fundic gland polyp in the distal esophagus, showing a variant allele frequency (VAF) of 40%. Subsequent analysis also detected the variant in the patient's buccal swab DNA (VAF 0.3%), while it was notably absent in multiple other tissue samples, including blood, urine, skin, and several additional samples from the proximal gastrointestinal tract. We explore several hypotheses that could explain these intriguing findings.
Uniparental disomy (UPD), the inheritance of two copies of a chromosome from one parent, can lead to recessive genetic disorders or imprinting effects. We report a case of autosomal recessive glycogen storage disease typ...Uniparental disomy (UPD), the inheritance of two copies of a chromosome from one parent, can lead to recessive genetic disorders or imprinting effects. We report a case of autosomal recessive glycogen storage disease type 4 (GSD IV) due to maternal UPD of chromosome 3, representing the first reported instance of UPD leading to this rare disorder. To avoid an unjustified claim of misattributed paternity, the possibility of UPD should always be kept in mind in cases with the unique finding of the homozygous pathogenic variant only present in one parent. This case highlights the critical role of genetic counseling in uncovering rare genetic conditions and emphasizes the need for continued awareness of UPD in clinical genetics.
Uniparental disomy (UPD) constitutes an unconventional mode of inheritance that disrupts the typical biparental genetic contribution and may result in phenotypic abnormalities. This report centers on a patient diagnosed...Uniparental disomy (UPD) constitutes an unconventional mode of inheritance that disrupts the typical biparental genetic contribution and may result in phenotypic abnormalities. This report centers on a patient diagnosed with Bartter syndrome Type 1, attributed to a homozygous pathogenic variant in unmasked by mosaic paternal UPD of chromosome 15. We hypothesize that this pattern (or constellation) emerged from a trisomy rescue event, resulting in two distinct cell lines. Concurrently, the unmasking of a pathogenic paternal variant by trisomy rescue resulted in the manifestation of Bartter syndrome Type 1. The maternally derived ring chromosome 15 and its impact on nondisjunction and UPD elucidate a unique etiology of Bartter syndrome. Furthermore, the presence of a pathogenic paternal variant underscores the pivotal role of trisomic rescue and paternal UPD in unveiling a recessive variant.
Deletions within the chromosomal locus 1p31.1 are rare, with only a limited number of documented cases. The typical clinical presentation includes intellectual disability, failure to thrive, and craniofacial abnormalitie...Deletions within the chromosomal locus 1p31.1 are rare, with only a limited number of documented cases. The typical clinical presentation includes intellectual disability, failure to thrive, and craniofacial abnormalities. Some cases may also present with cardiac, gastrointestinal, and genitourinary malformations. Variability in deletion size contributes to a broad spectrum of clinical phenotypes, and a comprehensive understanding of the syndrome's manifestations is still evolving. This case study aims to provide additional insights into 1p31.1 microdeletion syndrome, enhancing knowledge of its genetic and phenotypic characteristics to improve recognition by clinicians. Here, we report a case featuring a 14.385 Mb deletion isolated to the 1p31.1 region, encompassing 41 genes. The deletion manifested with microcephaly, distinctive facial morphology, hypotonia, developmental delay, bilateral cryptorchidism, and flat feet. Notably, our case also exhibited congenital thickening of the lingual and labial frenulum, a trait not typically associated with this deletion.
Neonatal liver disease is a broad entity. When it presents in conjunction with other abnormalities, it raises the question of a potential underlying genetic cause. Etiologies that were once difficult to diagnose are beco...Neonatal liver disease is a broad entity. When it presents in conjunction with other abnormalities, it raises the question of a potential underlying genetic cause. Etiologies that were once difficult to diagnose are becoming more readily identifiable with the arrival of next-generation sequencing. We present a rare cause of neonatal liver disease, a FOCAD gene variant, that was determined to be the most likely cause of an infant's liver disease and other findings. This case adds to only a few reports in the literature on this presentation in the neonatal period.