American Journal of Medical Genetics. Part A

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of paternal genes on chromosome 15. The Aberrant Behavior Checklist (ABC) is a standardized rating scale for assessing problematic behaviors in persons with developmental disabilities. Our study aims to describe ABC scores in youth with PWS and track their change over time. The analysis included 69 patients. Mean ABC scores were compared in four age groups (5-8, 9-12, 13-16, and 17-22 years). A statistically significant difference was found only in the Irritability subscale, with lower scores in the 5-8 age group compared to the 9-12 age group...

Alterations in the X-linked recessive DMD gene cause dystrophinopathies with a broad clinical spectrum most commonly ranging from Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to cardiomyopathy or intellectual disability. Carrier females are commonly unaffected but may show signs of dystrophinopathies. In addition, few asymptomatic male carriers with elevated creatine kinase levels have been described possibly related to deletions around exon 48. We now further support this assumed genotype-phenotype correlation by reporting an attenuated phenotype in a three-generation family with a deletion of exon 48 of the DMD gene with clinically unaffected carrier males and females...

Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population...

Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene...

Holoprosencephaly (HPE) results from a lack of cleavage of the prosencephalon. It has a complex etiology, resulting from chromosome abnormalities or single gene variants in the Sonic hedgehog signaling pathway. A single variant, p.Arg535Cys in CNOT1, has been described in HPE in association with pancreatic agenesis and neonatal diabetes. Here, we report on a case of HPE and p.Arg535Cys in CNOT1 without pancreatic agenesis where the patient presented with diabetes mellitus in adolescence. This case reinforces the role of CNOT1 in pancreatic development...

Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (ACCES, OMIM #619959) is an extremely rare multiple congenital anomalies syndrome caused by haploinsufficiency of the UBA2 gene. This syndrome presents with growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal problems including ectrodactyly, developmental dysplasia of the hip (DDH) and scoliosis, skin findings such as aplasia cutis, and some internal organ abnormalities. Our 13-year-old female patient and her 38-year-old father had a skeletal dysplasia phenotype with disproportionate short stature, bilateral DDH, mild epiphyseal involvement, scoliosis, and increased lumbar lordosis...

Vascular Ehlers-Danlos, Marfan and Loeys-Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers-Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric-based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections...

Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023...

Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 1000 adults. Most cases result from causative PKD1 or PKD2 variants. HNF1B, GANAB and ALG9 variants are also associated with ADPKD. Recent evidence indicates that monoallelic loss-of-function (LoF) IFT140 variants are a cause for non-syndromic ADPKD. We describe 368 patients with IFT140 LoF variants and a spectrum of phenotypic findings that support the association of IFT140 with PKD. We reviewed patients with an unknown cause for their cystic disease and those with heterozygous LoF IFT140 variants classified as pathogenic or likely pathogenic from a cohort that received genetic testing using a panel of 385 renal disease-associated genes...

No abstract text is available yet for this article.

There is an increasing recognition of the importance of diagnosing genetic conditions with an ever-growing list of genetic testing options. However, most providers do not have formal genetics training, which makes choosing the most appropriate test to order challenging. Our project sought to improve cytogenetic testing utilization in a tertiary care neonatal intensive care unit (NICU) through utilizing quality improvement techniques, specifically the Model for Improvement framework with rapid Plan-Do-Study-Act cycles...

BACKGROUND: Ectodermal dysplasias (EDs) are a heterogeneous group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. There are currently 49 recognized EDs with molecularly confirmed etiology. The EDs are very rare disorders, individually and in aggregate. Very little is published regarding the prevalence of these rare disorders. As a result of the genomics revolution, rare diseases have emerged as a global health priority...

Glycosylphosphatidylinositols (GPIs) are a type of glycolipid responsible for anchoring many important proteins to the cell membrane surface. Defects in the synthesis of GPIs can lead to a group of multisystem disorders known as the inherited GPI deficiencies (IGDs). Homozygosity for the c.-270C > G variant in the promoter of PIGM has been associated with a IGD subtype known as glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1). The several cases reported in the literature have been described to have a milder neurologic phenotype in comparison to the other IGDs and have been treated with sodium phenylbutyrate with some degree of success...

We describe a case in which a type 1 Gaucher patient developed ichthyosis weeks after starting substrate reduction therapy (SRT) with eliglustat. There are no reports of ichthyosis in the literature in enzyme replacement or SRT for Gaucher disease. Ichthyosis is seen with type 2 and 3 Gaucher disease, but not type 1. This raises the question: Why would a patient develop ichthyosis after starting SRT?

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct disorders typically associated with pathogenic variants in TSC1 and TSC2 for the former and PKD1 and PKD2 for the latter. TSC2 and PKD1 lie adjacent to each other, and large deletions comprising both genes lead to TSC2/PKD1 contiguous gene deletion syndrome (CGS). In this study, we describe a young female patient exhibiting symptoms of TSC2/PKD1 CGS in which genetic analysis disclosed two noncontiguous partial gene deletions in TSC2 and PKD1 that putatively are responsible for the manifestations of the syndrome...

GREB1-like retinoic acid receptor coactivator (GREB1L) gene is associated with autosomal dominant renal hypodysplasia/aplasia 3 (RHDA3) and deafness, autosomal dominant 80 (DFNA80). Among the GREB1L variants reported, most of them are missense or frameshift, while no pathogenic synonymous variants have been recorded. Classical theory paid little attention to synonymous variants and classified it as nonpathogenic; however, recent studies suggest that the variants might be equally important. Here, we report a 7-year-old girl with new symptoms of clitoromegaly, uterovaginal, and ovarian agenesis as well as right kidney missing...

Williams syndrome (WS) is a multi-system condition caused by the deletion of 25-27 coding genes on human chromosome 7. Irritability, gastrointestinal (GI) reflux and slow growth are commonly reported in infants with WS, but less data exist regarding GI concerns in older children and adults with the condition. This study evaluates 62 individuals with WS (31 children aged 3-17, and 31 adults aged 18-62) as well as 36 pediatric and adult controls to assess current and historical rates of common GI symptoms. Data were evaluated using a regression model including age, sex, self-reported race, and diagnosis...

Native American myopathy (NAM, also known as STAC3 disorder) (OMIM 255995) is an ultra-rare genetic disease impacting multiple body systems. The quality of life and caregiver burden associated with this condition remain poorly characterized. In this study, the Pediatric Quality of Life Inventory and a survey comprised of de novo questions concerning genetic testing, counseling, and caregiver burden were employed to investigate the health-related quality of life (HRQoL) in patients and caregivers with NAM. Study findings uncovered a concerning trend: patients with NAM experienced a notable decline in HRQoL, with reasons that warrant further investigation...

Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress...

Autosomal recessive spinocerebellar ataxias (SCARs) are a heterogeneous group of neurodegenerative disorders. VPS13D gene is currently the only gene associated with autosomal recessive spinocerebellar ataxia type 4 (SCAR4), also known as VPS13D dyskinesia. SCAR4 is a rare inherited disease, with only 34 reported cases reported worldwide. In this study, we reported three independent SCAR4 cases with adolescent onsets caused by five novel variants of the VPS13D gene. Each patient carried one frameshift and one missense variant: Patient 1 with c...