American Journal of Medical Genetics Part A最新文献

Heterozygous COL1A1 and COL1A2 gene variants are known to cause osteogenesis imperfecta (OI) in 90% of the patients in the Western and Japanese populations. Two previous Indian reports, a total of 49 patients, showed their proportion in the Indian population to be 44% and 71%. We studied a population of 210 children with a clinical diagnosis of OI and focused on the cohort of children with (likely) pathogenic COL1A1/COL1A2 variants. The prospective study describes the clinical, radiological, and genetic findings of 100 COL1A1/A2 variants. Phenotypic evaluation included the type of OI, fracture history, extraskeletal and skeletal features, pamidronate treatment, and its effect on bone density. Genotyping was assessed by clinical or targeted exome sequencing and validated by Sanger sequencing. One hundred patients, including affected siblings, out of 210 had COL1A1/A2 gene variants. No genetic cause was found in 25, and the remaining had causative variants in other OI-associated genes. In the group of 100 children with (likely) pathogenic COL1A1/A2 variants, the proportions of phenotypes 1, 3, and 4 were 24%, 44%, and 32%, respectively. Consanguinity was 10%, which was less when compared to the other OI-associated genes. The age of the first fracture was primarily at birth or before 6 months, particularly in severe types of OI such as Type III. Blue sclerae were observed in 84 patients, most commonly associated with OI Type I. Dentinogenesis imperfecta (DI) was present in 47 patients, typically seen in Types III and IV. Radiological features included Wormian bones in 58 patients, vertebral fractures in 46, and spine deformities in 16. Lower limb deformities were present in 90% of cases, with a higher prevalence in more severe forms of OI, while upper limb deformities were noted in 39%. Among the 22 patients receiving regular pamidronate therapy, there was a noticeable improvement in bone density, emphasizing the therapy's effectiveness, particularly in managing moderate to severe OI types. Genotypically, we report (likely) pathogenic 56 COL1A1 and 46 COL1A2 variants, including 21 novel variants. Of the 66 missense variants, 29 were in COL1A1 and 37 in COL1A2 genes. Of these, 60 were glycine substitutions (28 in COL1A1 and 32 in COL1A2) in the triple helix, the commonest being glycine to serine, associated with OI Type 3 in 28 individuals. The report highlights that 47.6% (100 out of 210 patients) of COL1A1 and COL1A2 gene variants were found in our cohort who underwent genetic analysis. This percentage is notably lower compared to other populations, where the percentage of identified COL1A1/2 variants has been reported to be higher.

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a germline vascular dysplasia that is typically characterized by cutaneous capillary malformations and central nervous system arteriovenous malformations (AVM). We report an atypical presentation of CM-AVM2 featuring a giant coronary fistula. A 22-day-old male exhibited a cardiac murmur, leading to the discovery of a large fistula from the left circumflex coronary artery. The patient developed left eye exophthalmos due to a left-sided basilar to pontomesencephalic vein fistula. Genetic testing demonstrated a previously reported pathogenic ephrin type B-receptor 4 (EPHB4) variant c.175G>A, p.Glu59Lys, suggesting a diagnosis of CM-AVM2 syndrome. A variant of uncertain significance in GATA-binding factor 2 (GATA2) c.1289C>T, p.Ala430Val was also identified. Due to residual enlargement of the left coronary artery following fistula occlusion, the patient was initiated on warfarin and aspirin for dual anticoagulation and antiplatelet therapy. This uncommon presentation may warrant cardiac imaging for patients with CM-AVM syndrome presenting with a murmur or other cardiac symptoms. Further investigation is necessary to determine the incidence of cardiac involvement in patients with CM-AVM syndrome.

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by impaired catabolism of branched-chain amino acids (BCAAs). The genes BCKDHA, BCKDHB, DBT, and DLD encode the subunits of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which is essential for BCAA metabolism. Catalytic subunits are BCKDHA, BCKDHB, DBT, and DLD, whereas the regulator subunits are PPM1K and BCKDK. PPM1K plays a critical role by dephosphorylating and activating this enzyme complex. Pathogenic variants in the PPM1K gene cause an extremely rare, mild form of MSUD. Here, we report an 8-year-old male patient with a mild form of MSUD putatively caused by a novel homozygous variant in PPM1K. The patient presented with mild dysmorphic features, delayed speech, relative microcephaly, and overweight, all considered familial phenotypic traits. Laboratory findings revealed mildly elevated plasma branched-chain amino acids, mild lactic acidemia, and a slight increase in urinary keto acids. Exome sequencing identified a novel homozygous missense variant, c.925A>G p.(Ile309Val), in the PPM1K gene. This case represents the third reported patient with a mild form of MSUD associated with the first reported missense variant in the PPM1K gene in the literature, further expanding the clinical and genetic spectrum of PPM1K-related disorders.

We report a 4-year-old Dinè (Navajo) boy who presented with acute respiratory distress, elevated creatine kinase, anemia, and progressive encephalopathy. He was subsequently diagnosed with a rare inborn error of metabolism, phosphoglycerate kinase deficiency, associated with the previously reported pathogenic variant in PGK1, c.491A>T (p.D164V). His presentation is unique and differs from previous cases of this variant. While other children have demonstrated neurologic symptoms with hemolytic crises, our patient experienced severe neurologic symptoms in addition to marked rhabdomyolysis with chronic hemolysis. This is also the first case reported in the Dinè population, an underrepresented minority.

Blepharocheilodontic syndrome (BCD syndrome) is an autosomal dominant condition characterized by cleft lip/palate, distinct eyelid abnormalities, and ectodermal changes affecting hair and teeth. This report presents a novel case of CTNND1-related BCD syndrome in a 3-year-old female. In addition to the typical features, including unilateral cleft lip/palate and eyelid malformations, the patient exhibited a duplex kidney, ureterocele, and a bicornuate uterus-phenotypic traits not previously associated with BCD syndrome. Whole exome sequencing identified a de novo heterozygous pathogenic splice site variant in CTNND1, confirming the diagnosis. The presence of these additional urogenital anomalies suggests a potential expansion of the BCD syndrome phenotype. This case highlights the need for further investigation into the spectrum of anomalies associated with BCD syndrome, recommending ultrasound evaluation of the urinary tract in newly diagnosed individuals.

An illustration of the importance of manual data review for identifying rare intronic variants adjacent to homopolymers is presented here. A 14-year-old male with Niemann-Pick Type C disease confirmed biochemically was only found to have a heterozygous pathogenic variant by molecular analysis. A manual review of the Next Generation Sequencing (NGS) data identified a c.709C>T; p.Pro237Ser variant, which was likely not reported initially because it is consistently classified as benign or likely benign. A rare association of the c.709C>T variant with a second intronic NPC1 variant (c.1947 + 5G>C) leading to the use of a cryptic splice donor site has been reported before. Further evaluation with Sanger sequencing detected the c.1947 + 5G>C variant as the second causative variant in this patient. Detection of a second allelic change in autosomal recessive inborn errors of metabolism and other genetic disorders is vital in establishing a diagnosis, initiating new therapies, and testing at risk family members. The case presented here illustrates a rare intronic splice site NPC1 variant that may not be readily detected by current short-read NGS technologies due to the downstream homopolymers and should be evaluated regularly, especially in the presence of another heterozygous variant.

Krabbe disease (KD), or globoid cell leukodystrophy, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in galactocerebrosidase (GALC), leading to psychosine (galactosylsphingosine) accumulation and myelin damage. The natural history of the attenuated form is poorly understood, but it typically presents with spastic paraparesis, progressing more slowly than the early-onset or infantile variant. Diagnosis relies on a high index of clinical suspicion, imaging studies, biochemistry, and molecular analysis. Magnetic resonance imaging (MRI) demonstrates characteristic corticospinal tract involvement, while cerebrospinal fluid analysis can reveal elevated protein levels. We present a case of late-onset KD in a 55-year-old male with a novel pathogenic GALC variant, aiming to highlight the features and investigation findings that should prompt consideration of the diagnosis. In addition, we describe the course of illness, emphasizing the importance of multi-disciplinary team (MDT) input in patient care and the role of novel blood-based and imaging biomarkers.