American Journal of Medical Genetics Part A最新文献

PGM2L1 is a crucial enzyme exhibiting glucose 1,6-bisphosphate synthase activity, with predominant expression in brain tissue. In 2021, biallelic pathogenic variants in the PGM2L1 gene were first linked to a neurodevelopmental disorder characterized primarily by developmental delay in four pediatric cases. In this study, we aimed to delineate the adult phenotype associated with the PGM2L1-related neurodevelopmental disorder and to perform functional characterization of the identified variant. Two siblings presenting with neurodevelopmental delay were evaluated clinically and genetically. Exome sequencing of the older sibling revealed a homozygous nonsense variant, c.277C>T p.(Gln73Ter), in the PGM2L1 gene. This variant results in truncation leading to loss of key functional domains including the substrate binding site, catalytic active site, and protein stability regions. Quantitative analysis demonstrated a significant reduction in PGM2L1 gene expression in both siblings compared to controls (p value < 0.01). Unlike previously reported pediatric cases, the second sibling exhibited additional features including scoliosis, renal anomaly, tooth loss, hypothyroidism, bladder trabeculation, anhidrosis, and temperature intolerance, notably in the absence of obesity. These cases represent the first detailed description of an adult phenotype associated with a biallelic pathogenic variant in PGM2L1, expanding the clinical spectrum of this neurodevelopmental disorder.

Raine Syndrome (MIM #259775) is an autosomal recessive osteosclerotic disorder due to biallelic variants in the FAM20C gene. It is classified into two subtypes based on perinatal lethality. Here, we report an 18-year-old male who presented with dental problems in childhood and subjective gait instability, followed by an incidental finding of hypophosphataemia and multiple-level spinal stenosis. Examination showed characteristic features including a high forehead, midface hypoplasia, prognathism, amelogenesis imperfecta, brachydactyly and bulbous finger tips, and further biochemical workup revealed a low 1,25-dihydroxyvitamin D level and an elevated FGF23 level. Exome sequencing identified compound heterozygous NM_020223.4 c.1487C > T, p.(Pro496Leu), and c.1375C > T, p.(Arg459Cys) likely pathogenic variants in the FAM20C gene, with the latter being a novel variant. This case report therefore expands the genetic and phenotypic spectrum of non-lethal Raine Syndrome, and underscores the importance of genetic evaluation in hypophosphatemic patients with dysmorphic features.

The Ras/mitogen-activated protein kinase (RAS/MAPK) pathway regulates cell proliferation, and dysregulation of this pathway has been linked to the increased risk of malignancy in a subset of disorders known as RASopathies (e.g., NF1, Costello syndrome, Noonan syndrome). However, reports of malignancy are rare in cardiofaciocutaneous (CFC) syndrome, which is caused by heterozygous pathogenic variants in BRAF, MAP2K1, MAP2K2, and KRAS. Somatic pathogenic variants in BRAF are one of the most common drivers of Langerhans cell histiocytosis (LCH), a neoplastic disorder that can present with lesions in a variety of locations. However, despite the association of somatic BRAF variants and LCH, individuals with CFC syndrome are not thought to have higher rates of LCH. Here, we report two individuals with CFC syndrome and LCH and review the literature examining this potential association.

Turner syndrome, a chromosomal disorder, causes short stature, pubertal arrest, amenorrhea, and infertility in females. Prevalence estimates vary widely; however, reliable estimates are important for public health initiatives. Therefore, a meta-analysis was undertaken. From a total of 875 English-language studies identified for full-text screening in MEDLINE and Embase by two independent researchers using predefined criteria, data were extracted from 28 studies, which were also evaluated for quality; 19 and 8 were selected for the birth and point/period prevalence meta-analyses, respectively (three studies common to both). A random-effects model was used to calculate a pooled effect size. Heterogeneity was measured using Cochran's Q, Higgins I², Tau-squared, and Tau. The birth prevalence meta-analysis yielded a pooled estimate of 31.5 (95% CI: 18.2-54.7) per 100,000 female live births. Studies from Europe (compared to Asia) and those with a lifetime case ascertainment period (compared to first year) reported significantly higher birth prevalence. Meta-regression analysis indicated that studies with lifetime case ascertainment had 2.69 times higher prevalence. Case ascertainment period, diagnostic method, and geography accounted for ~90% of the variation in the birth prevalence estimates across studies. The pooled estimate of point/period prevalence was 23.1 (95% CI: 11.4-46.8) per 100,000 females.

We report a 15-year-old female with hypoplastic left heart syndrome and a strong family history of congenital heart defects. Quad genome sequencing was performed following negative chromosomal microarray and congenital structural heart disease gene panel testing, revealing a heterozygous 144 kb deletion encompassing exons 4-14 of RBFOX2, the entirety of the APOL5 gene, and exon 3 of APOL6 in all affected family members. Although RBFOX2 has been implicated in causing hypoplastic left heart syndrome in animal models, and variants in this gene are enriched in patients with congenital heart disease, this report establishes loss-of-function variants in RBFOX2 as an autosomal dominant cause of hypoplastic left heart syndrome. Furthermore, this case highlights the power of genome sequencing in identifying causative variants in patients who have received nondiagnostic array and panel testing.

Noonan Syndrome (NS) is a clinically and genetically heterogeneous condition characterized by typical facial dysmorphisms, short stature, congenital heart defects, and developmental delays. While variants in genes such as PTPN11, SOS1, and RAF1 account for most genetically confirmed cases, diagnosis is challenging due to phenotypic overlap with other syndromes. In this retrospective study, we reviewed 192 patients with a clinical diagnosis of NS at a single tertiary center. Genetic diagnosis of NS was confirmed in 133 patients (69.4%) and diagnosis of non-NS RASopathies was confirmed in 5 patients via targeted RASopathy panels. Exome sequencing (ES) was performed in 20 of the undiagnosed patients. In six cases, alternative genetic diagnoses were established due to variants in SETD5, BRPF1, DPH1, ACTB, CREBBP, and GATA4, genes associated with syndromes presenting overlapping phenotypes with NS. Our findings emphasize the utility of a hypothesis-free approach that uses phenotypic features to prioritize variants in resolving diagnostic uncertainty in NS-like presentations. These findings also highlight the need to broaden differential diagnoses beyond RASopathies when genetic confirmation of NS cannot be established.

Simpson-Golabi-Behmel syndrome 1 (SGBS1) is a rare X-linked recessive condition characterized by overgrowth and multiple congenital anomalies. SGBS1 is caused by damaging variants in the Glypican-3 (GPC3) gene. The GPC3 protein plays a crucial role in cellular signaling processes including cell growth, embryogenesis, and differentiation. Functional maturation of GPC3 occurs via several steps of post-translational modification (PTM) and processing to enable its transport to, and anchorage on, the plasma membrane. GPC3 positively modulates the canonical Wnt signaling pathways, while negatively regulating the Hedgehog signaling pathways. Loss-of-function is the underlying mechanism of disease for SGBS1, with a minority of reported pathogenic variants being missense substitutions. We report a family with four affected individuals in whom a novel GPC3 missense variant was identified via exome sequencing: NM_004484.3: c.695C>A; p.(Ala232Asp). The variant segregated with disease in the family, and functional studies conducted using HEK293T cells demonstrate a distinct mis-localization of the mutant GPC3 protein, thereby supporting the pathogenicity of this novel missense variant. These findings allowed for an upgraded classification of the missense variant from a variant of uncertain significance to that of likely pathogenic.

Smith-Magenis syndrome (SMS, OMIM 182290) is a complex syndromic diagnosis marked by neurobehavioral differences and distinct facial dysmorphisms, caused by haploinsufficiency of the retinoic acid-1 (RAI1) gene either by a pathogenic sequence variant or deletion at chromosome 17p11.2 involving a portion or all of this gene. Dysmorphisms may include a broad square face and brachycephaly, heavy eyebrows, a full mouth with an everted upper lip, and early micrognathia evolving to prognathism after excessive relative mandibular growth. All patients with SMS have variable global cognitive impairment, greatest in speech/language, disturbed sleep patterns, and distinct behaviors including self-injury, food foraging, and abnormal oral intake regulation, hyperactivity, and aggression. Short stature and central obesity are common in patients with SMS, and reference curves are needed to assess growth in clinical care and research endeavors. After IRB approval, anthropometry (including length/height, weight, head circumference) was collected via direct patient encounter, parental report from external medical encounters, and extraction from medical records. Utilizing polynomial smooth splines with a B-spline basis and variable windows depending on age, sex-specific length/height and weight curves were created, including 5th, 50th and 95th percentile lines for 0 through 15 years. Head circumference data were pooled from males and females to create 5th, 50th, and 95th percentile lines for 0 through 5 years. Nearly 6000 length/height, weight, and head circumference measurements from 190 patients with SMS from birth through adulthood were gathered. Length/height and weight data were plotted against age from birth through 15 years to create new length/height-for-age and weight-for-age curves by sex. Similar processes were employed to construct head circumference-for-age curves from birth through 5 years, combining data from both sexes into one figure. Final adult height was derived from the maximum adult height for each subject over the age of 18 years. The curves included in this article represent the first set of standardized growth curves for individuals with SMS. As such, they will permit clinicians to monitor and set expectations for linear growth, weight gain, and cranial growth in individuals with SMS.