Recurring germline mosaicism in a family due to reversion of an inherited derivative chromosome 8 from an 8;21 translocation with interstitial telomeric sequences.

BACKGROUND: Mosaicism for chromosomal structural abnormalities, other than marker or ring chromosomes, is rarely inherited. METHODS: We performed cytogenetics studies and breakpoint analyses on a family with transmission of mosaicism for a derivative chromosome 8 (der(8)), resulting from an unbalanced translocation between the long arms of chromosomes 8 and 21 over three generations. RESULTS: The proband and his maternal half-sister had mosaicism for a der(8) cell line leading to trisomy of the distal 21q, and both had Down syndrome phenotypic features. Mosaicism for a cell line with the der(8) and a normal cell line was also detected in a maternal half-cousin. The der(8) was inherited from the maternal grandmother who had four abnormal cell lines containing the der(8), in addition to a normal cell line. One maternal half-aunt had the der(8) and an isodicentric chromosome 21 (idic(21)). Sequencing studies revealed microhomologies at the junctures of the der(8) and idic(21) in the half-aunt, suggesting a replicative mechanism in the rearrangement formation. Furthermore, interstitial telomeric sequences (ITS) were identified in the juncture between chromosomes 8 and 21 in the der(8). CONCLUSION: Mosaicism in the proband, his half-sister and half-cousin resulting from loss of chromosome 21 material from the der(8) appears to be a postzygotic event due to the genomic instability of ITS and associated with selective growth advantage of normal cells. The reversion of the inherited der(8) to a normal chromosome 8 in this family resembles revertant mosaicism of point mutations. We propose that ITS could mediate recurring revertant mosaicism for some constitutional chromosomal structural abnormalities.

CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.

PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort. METHODS: We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders. RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses. CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.

Temporospatial and kinematic gait alterations during treadmill walking with body weight suspension.

Our purpose was to analyze the effects of selected levels of body weight support (BWS) on lower extremity kinematics of normal subjects at a predetermined treadmill speed. Seventeen non-disabled volunteers walked on a treadmill at 1.25 ms(-1). Temporospatial and kinematic data were collected while various support levels were applied (Minimal, 10, 30, 50 and 70% BWS). Compared to 10% BWS, significant temporospatial and kinematic changes were induced by 50 and 70% BWS. Fewer differences were induced by 30% BWS compared to 10% BWS. We concluded that gait patterns of unimpaired subjects are significantly changed by 50 and 70% BWS.

Compensatory mechanisms in anterior cruciate ligament deficiency.

The literature cites numerous studies involving the analysis of movement patterns in anterior cruciate ligament deficient (ACLD) patients. Although several in vivo biomechanical studies have shown that ACLD patients develop protective mechanisms against degenerative diseases, it seems that these adaptations fail to protect the knee from future pathology. Some authors state that ACLD patients adapt to the injury by avoiding quadriceps contraction during gait when the knee is near full extension. However, others have found increased hamstrings and decreased gastrocnemius activity, which normally contribute to the stability of the knee. It seems that further in vivo biomechanical investigation is required to understand the mechanisms of pathological knee joint motions and develop rehabilitation programs, which would delay the progress of developing long-term degenerative diseases.