Analysis of a Chinese pedigree affected with Meckel syndrome due to variants of TMEM67 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a Chinese pedigree affected with Meckel syndrome.@*METHODS@#A pedigree with a history of three consecutive adverse pregnancies which presented at the First Affiliated Hospital of Zhengzhou University on August 31, 2017 was selected as the study subject. Clinical data of the pedigree were collected. High-throughput sequencing was carried out to screen for variants of ciliopathy-related genes in the third fetus following induced abortion, and candidate variant was verified by Sanger sequencing.@*RESULTS@#The first pregnancy of the couple had ended as spontaneous abortion, whilst the fetus of the second pregnancy was suspected for having ciliopathy, though no genetic testing was carried out following elected abortion. The fetus of the third pregnancy was suspected for having ciliopathy, and high-throughput sequencing and Sanger sequencing had shown that the fetus had harbored compound heterozygous variants of the TMEM67 gene, including c.978+1G>A from the father and c.1288G>C (p.D430H) from the mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.978+1G>A was classified as a pathogenic variant (PVS1+PM2_Supporting+PP5), whilst the newly discovered c.1288G>C (p.D430H) was classified as a likely pathogenic variant (PM2_Supporting+PM3+PM5+PP3).@*CONCLUSION@#The c.978+1G>A and c.1288G>C (p.D430H) compound heterozygous variants of the TMEM67 gene probably underlay the three consecutive adverse pregnancies suspected for ciliopathy in this pedigree. The discovery of c.1288G>C (p.D430H) has also expanded the mutational spectrum of the TMEM67 gene.

Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice / 医学前沿

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

El intersticio pulmonar y sus enfermedades en la infancia y adolescencia. Disquinesia ciliar primaria / Pulmonary interstitium illnesses during Infancy and adolescence. Primary ciliary diskinesia

Introducción. Sobre la base de un caso clínico, se presenta la descripción del cuadro intersticial por disquinesia ciliar primaria de una paciente, desde los dos meses de edad (conforme el relato de la familia) hasta los 16 años, cumplidos en el año 2021. Método. Se realizó una evaluación clínica con extensos estudios para descartar otras patologías similares. El diagnóstico definitivo fue determinado por el estudio genético para disquinesia ciliar primaria (DQCP) y otros defectos genéticos informados por el laboratorio Ambrygen, Estados Unidos. Objetivos. Describir detalladamente la evolución de la paciente durante quince años, con énfasis en los estudios mencionados. Presentar la evolución desde el nacimiento hasta el año 2021 de una recién nacida con distress respiratorio (asistencia respiratoria mecánica durante diez días), con neumonía a los pocos días de nacer y con otitis, sinusitis y neumonías recurrentes, que llega a la fecha con una calidad de vida óptima, sin sinusitis, otitis ni neumonías y con espirometría normal. Su capacidad física para realizar cualquier actividad deportiva de esfuerzo importante señala la extraordinaria respuesta a los tratamientos. Presentar los hallazgos de genética, microscopía electrónica y estudios de barrido ciliar. Resultados. Confirmado su diagnóstico de DQCP, presentamos su seguimiento actualizado hasta el año 2021. La DQCP debe ser sospechada en recién nacidos y lactantes ante la persistencia de neumonías, otitis, sinusitis y bronquitis recurrentes. (AU)

Introduction. On the basis of a clinical case, a description of the interstitial picture due to primary ciliary dyskinesia of a patient from two months of age (according to the family's report) to 15 years of age, completed in the year 2021 is presented. Methodology. Clinical evaluation based on multiple studies to rule out another similar pathology. Final diagnosis was established through genetic studies for primary ciliary diskinesia (PCDK). (Ambrygen-USA). Objective. To describe clinical, laboratory and spirometric evolution of this patient during fifteen years. Also to bedescribe evolution since birth up to the year 2021. The patient was born with respiratory distress (needed mechanical ventilation for ten days), with pneumonia a few days after delivery, and with sinusitis and recurrent pneumonia. Finally, she has now a high quality of life. No sinusitis, otitis or pneumonia and normal spirometry. She´s able to perform heavy physical efforts. We present the genetic and electron microscopy (video) studies to observe ciliary beating. Results. After confirming your DQCP diagnosis, we present your updated follow-up until 2021. DQCP should be suspected in newborns and infants in the presence of recurrent pneumonia, otitis sinusitis and bronchitis. (AU)

Diagnóstico genético en disquinesia ciliar primaria: revisión bibliográfica / Genetic diagnosis in primary ciliary dyskinesia: literature review

La disquinesia ciliar primaria (DCP) corresponde a una enfermedad genética heterogénea, que se produce por una alteración estructural o funcional de los cilios. Es de difícil diagnóstico tanto por su variada sintomatología como por la existencia de métodos de screening y diagnóstico complejos. El método que hasta ahora ha sido considerado como gold standard es el análisis de la estructura ciliar por medio de la microscopía electrónica de transmisión (MET). Esta técnica tiene limitaciones porque permite analizar un número limitado de axonemas ciliares y puede excluir del diagnóstico a pacientes con axonema normal pero con alteración funcional y clínica clásicas. En los últimos años se han desarrollado métodos diagnósticos sobre la base de un mejor conocimiento de la estructura proteica de los cilios, de los genes que codifican estas proteínas y de las mutaciones asociadas a DCP. Estos nuevos métodos consisten en un análisis genético y un estudio de la expresión de proteínas ciliares en los pacientes afectados. Esta publicación tiene como objetivo realizar una revisión de la fisiopatología de la DCP, los métodos diagnósticos actuales y resumir el desarrollo del diagnóstico genético en la literatura internacional y su posible aplicación en nuestro medio.

Primary cilliary dyskinesia (PCD) is an heterogeneous genetic disease caused by a structural and/or functional alteration of the ciliary skeleton. It is a diagnostic challenge due to its protean clinical presentation and to the complexity of screening and diagnostic methods. The method hitherto regarded as the gold standard is the analysis of ciliary structure by transmission electron microscopy (TEM). This presents limitations because analyzes a limited number of ciliary axonemes, and may exclude cases with typical functional and clinical presentation. In recent years new diagnostic methods have been developed based on novel knowledge of the structural ciliary proteins, the genes encoding these proteins and mutations associated to DCP. These new methods include genetic analysis and the study of protein expression in cilia of the affected patients. This paper reviews DCP pathophysiology, the current diagnostic methods applied, and summarizes the international literature regarding the diagnosis of DCP based on genetic screening.

Síndrome de disquinesia ciliar / Cilliary dyskinesia syndrome

Se describe la historia médica de dos hermanos mellizos, que sufrían de tos crónica desde el nacimiento y que presentaban ausencia de los senos frontales, sinusitis maxilar, bronquiectasias y azoospermia, sin "situs inversus". El estudio de la estructura de la cilia de la mucosa bronquial con el microscopio electrónico demonstró, en uno de los pacientes, la ausencia de los brazos de fuerza