Noninvasive prenatal diagnosis of duchenne muscular dystrophy in five Chinese families based on relative mutation dosage approach

Background Relative haplotype dosage (RHDO) approach has been applied in noninvasive prenatal diagnosis (NIPD) of Duchenne muscular dystrophy (DMD). However, the RHDO procedure is relatively complicated and the parental haplotypes need to be constructed. Furthermore, it is not suitable for the diagnosis of de novo mutations or mosaicism in germ cells. Here, we investigated NIPD of DMD using a relative mutation dosage (RMD)-based approach—cell-free DNA Barcode-Enabled Single-Molecule Test (cfBEST), which has not previously been applied in the diagnosis of exon deletion. Methods Five DMD families caused by DMD gene point mutations or exon deletion were recruited for this study. After the breakpoints of exon deletion were precisely mapped with multiple PCR, the genotypes of the fetuses from the five DMD families were inferred using cfBEST, and were further validated by invasive prenatal diagnosis. Results The cfBEST results of the five families indicated that one fetus was female and did not carry the familial molecular alteration, three fetuses were carriers and one was male without the familial mutation. The invasive prenatal diagnosis results were consistent with those of the cfBEST procedure. Conclusion This is the first report of NIPD of DMD using the RMD-based approach. We extended the application of cfBEST from point mutation to exon deletion mutation. The results showed that cfBEST would be suitable for NIPD of DMD caused by different kinds of mutation types.

A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.

Psychiatric Onset Alexander Disease: An Important Challenge in Neuropsychiatric Diagnosis

Introduction: Alexander disease is a heterogenous group of diseases with various manifestations based on age of disease onset. This rare leukodystrophy syndrome with mutations in GFAP Gene could present with developmental delay and seizure in infantile form to ataxia and bulbar palsy in adulthood. However psychiatric symptoms are not well-defined and usually evaluate after disease diagnosis not before disease investigations. Case report: Our patient is a fifty-two-year-old Iranian woman with history of depression from about 17 years ago, suicidal attempt two years ago and ingestion a large amount of opium with the intention of suicide 2 months ago who was presented with disorientation and probably delirious state in the last interview. Eventually in comprehensive investigations, white matter hyperintensity and leukodystrophy was diagnosed and ultimately to determine the cause of these changes with gene study, whole and Exon deletion of GFAP Gene Late Onset Alexander disease was determined. Conclusion: Neurological-onset manifestation of Alexander disease specifically late onset form is the most common clinical picture of disease and was seen in about 90% of patients but psychiatric symptoms are not well-known and psychiatric- onset disease was not described yet. On the other hand, various Gene Mutation were described in Late Onset Alexander Disease, however large whole Exon deletion which was revealed in our patient is a novel mutation and significantly need to be declared. Here authors describe a late onset Alexander disease with psychiatric onset symptoms and novel large Exon deletion in GFAP Gene.