Clinical Genetics最新文献

This study is aimed at determining the spectrum of congenital heart disease associated with distal 22q11.22-23 deletions flanked by low copy repeats, LCR22 D-H. We analyzed cardiology findings in 128 unrelated individuals with distal LCR22 D-H deletions. A total of 62 were newly described and 66 were derived from previous reports. We found that deletions which included LCR22-D as the proximal endpoint were the most prevalent in the cohort (104/128, 81.3%). Clinically relevant congenital heart disease was identified in 48 individuals (37.5%, 95% CI 29%-46%), which is lower than the prevalence reported for typical, proximal LCR22 A-D deletions (p = 3.7E-4), especially for conotruncal defects (13/128, 10.2%; p = 7.1E-13). Mild to moderate CHD predominated, including ventricular septal defects (22/128), bicuspid aortic valve (9/128) and mild cardiomyopathy (3/128). Persistent truncus arteriosus was the most prevalent (n = 8/13) conotruncal heart defect, but other anomalies also occurred in singleton cases. These findings support the need for cardiac evaluation in all individuals with distal 22q11.22-23 deletions, increased use of clinical genetic testing in syndromic individuals with these findings, and molecular studies in model systems. The results demonstrate that reduced gene dosage of distal 22q11.21-23, particularly within the D-E region including MAPK1 and HIC2 convey risk for CHD.

This case highlights the complexity of diagnosing dual rare metabolic diseases and the importance of genetic testing in uncovering novel pathogenic variants. It has also contributed to expanding the clinical manifestation spectrum of B4GALT1-CDG, which is an ultra-rare disorder.

A patient of intellectual developmental disorder with autism and macrocephaly (IDDAM) caused by a novel CHD8 mutation developed adult-onset compulsive behaviors in addition to the core phenotype in early life. This case expands the clinical and genotypic spectrums of IDDAM which may inspire future studies on genotype-phenotype correlation and the disease course.

Pathogenic germline variants in DICER1 predispose to pleuropulmonary blastoma, multinodular goitre, embryonal rhabdomyosarcomas of the uterine cervix, ovarian Sertoli-Leydig cell tumour and a broader spectrum of pathologies. Here, we report a 35-year-old female with diagnoses of pineoblastoma, embryonal rhabdomyosarcoma, leiomyosarcoma, two meningiomas, and a germline DICER1 c.4206+1G>C, p.(?) variant. The variant was classified as a variant of unknown significance (VUS) based on the current ACMG/AMP gene-specific DICER1 guidelines. Additional functional analysis showed that the variant clearly abrogates the function of DICER1 and therefore PS3_Supporting evidence is included in the classification. Based on this the variant is reclassified as likely pathogenic. Moreover, our data suggest that the current ACMG/AMP gene-specific DICER1 guidelines should be modified in relation to the level of evidence strength (moderate to strong/very strong) for exon 22 skipping as well as to the use of the functional evidence (PS3) code.

FAM20B encodes glycosaminoglycan xylosylkinase, a key enzyme in proteoglycan biosynthesis. Biallelic pathogenic variants have only recently been linked to skeletal dysplasia. We report two pregnancies from one couple, resulting in three fetuses (twin sibs and younger sib) with severe skeletal anomalies. Prenatal findings included enlarged nuchal translucency, short bowed and dislocated limbs, intrauterine growth restriction, and multiple malformations. Intra-uterine fetal death occurred in Probands 1 and 2, and neonatal death of Proband 3. Postnatally, all three probands showed limb shortening with joint (sub)luxations and contractures, and craniofacial dysmorphisms. SNP-array and exome analysis revealed compound heterozygosity for two novel FAM20B variants: a paternal ~8 kb deletion encompassing the terminal exon and a maternal missense variant (p.Arg290Cys) at an evolutionary conserved position. The same amino acid residue was previously affected in a child with a milder phenotype. In silico modeling supports a destabilizing effect of the missense change on protein structure, especially due to the loss of a salt bridge essential for catalytic function. This report describes the prenatal phenotype of FAM20B-related dysplasia and can help establish the phenotypic spectrum of the disorder. It further supports the essential role of FAM20B in early skeletal development.

Hereditary spastic paraplegia (HSP) is a neurogenetic disorder characterized by progressive, length-dependent degeneration of the upper motor neurons. We investigated 112 Greek HSP index cases collected over more than 25 years from all regions of the country, using a combination of next generation sequencing and multiplex ligation-dependent probe amplification. In total, we identified a causative variant in 68 patients, corresponding to a diagnostic yield of 60.7%. The diagnostic yield was 62.8% in autosomal dominant HSP, 77.8% in autosomal recessive HSP and 50.0% in sporadic cases. We identified 7 novel causative variants in SPAST, SPG7, and CYP7B1. We found causative variants in a total of 18 different genes. The most commonly involved genes, affecting more than one family, were SPAST (25.0%), SPG11 (12.5%), CYP7B1 (3.6%), SPG7 (3.6%), KIF5A (2.7%), ABCD1 (1.8%) and PSEN1 (1.8%). Variants in ATL1, REEP1, BSCL2, PLP1, WASCHC5, AP5Z1, CYP27A1, SOD1, POLR3A, GFAP and ARG1 were identified in single families. This study presents a comprehensive overview of the phenotypic and genotypic spectrum of HSP in the Greek population, expanding previous data, and contributing to the characterisation of further pathogenic variants linked to HSP.

Primary ciliary dyskinesia (PCD) is a genetic disease caused by variants affecting more than 50 cilia genes. We report the prevalence and distribution of all known and novel variants in children with PCD in Qatar. The cohort included 28 children: 16 Qatari, 3 Egyptian, 2 Tunisian, 1 Sudanese, 1 Algerian, 1 Pakistani, 2 Iranian, and 2 Indian. Consanguinity rate was 82.1%. Median age at diagnosis was 7.5 years (IQR: 0.6-11.8). Situs inversus was present in 7 (25%) patients, chronic cough in 25 (89.3%), chronic sinusitis in 17 (60.7%), and bronchiectasis in 16 (61%). Median FEV1 was 71% (IQR: 58%-82%), FVC was 80% (IQR: 74%-91%), and FEV1/FVC ratio was 79% (IQR: 68%-84%). The most frequent variant in native Qataris was c.5924+1G>C in DNAH11 (seven patients). Eight novel variants were found in the cohort: c.6565C>T in DNAH11 (two patients); c.368-369del in DNAAF3 (one patient); c.357G>A in DNAFF2 (one patient); c.278G>A in DNAAF2 (one patient); c.1666-9C>G (intronic) in CCDC39 (two patients); c.9105+2T>C (splice donor) in DNAH5 (two patients); c.8647+3A>G (intronic) in DNAH5 (two patients); c.916G>T in ODAD4 gene (two patients). Wide genetic variation was found among PCD children in Qatar, including several novel variants, reflecting their ethnic diversity. Genetic variation was less among native Qatari patients due to high consanguinity.

To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencing data from 280 CHH probands, we identified 15 potential splice-site variants in CHD7, ANOS1 and FGFR1 by using in silico software. The functional consequences of these variants were analyzed by the minigene assay or RT-PCR analyses of RNA taken from the peripheral lymphocytes. Detailed phenotyping was performed in the CHH patients harboring deleterious variants and their available family members. 11 out of 15 potential splice-site variants were demonstrated to cause mis-splicing, resulting in loss of function through deletion, insertion or frameshift of amino acids in the proteins. Most patients with deleterious splice-site variants in CHD7, ANOS1, FGFR1 presented with gene-specific non-reproductive phenotypes, confirming the pathogenic contribution of these variants to CHH. Our study indicated that splice-site variants in CHD7, ANOS1, FGFR1 underlie the genetic basis of ~3.9% of CHH patients, warranting the inclusion of potential splice-site variants for genetic diagnosis and counseling of CHH.

Dominant mutations in the calcium permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically result in skeletal dysplasia or peripheral neuromuscular disease. However, the full spectrum of TRPV4-related phenotypes remains incompletely defined. This study systematically reviewed the clinical and genetic features of 10 Chinese patients harboring various TRPV4 variants. In the cohort, six patients were diagnosed with spondylometaphyseal dysplasia Kozlowski type (SMDK) and four patients with metatropic dysplasia (MD). The most common features involved spinal deformity (platyspondyly, kyphosis or scoliosis), and lower-limb malalignments (genu varum, genu valgum, or leg-length discrepancy). Two patients with MD had neurological deficits. The R594H and P799R substitutions were the most recurrent variants in our study. A novel variant (c.1628T>G, p.L543R) in the S2-S3 loop was identified. The study seeks to improve diagnostic precision by combining genetic and radiographic assessment, and highlights the importance of early spinal surveillance and multidisciplinary care to prevent neurological complications underlying TRPV4-mediated disorders.