LAMP2 exon‐copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected?

Abstract

Danon disease (DD) is an X-linked disorder caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene (Xq24). DD is characterized by cognitive deficit, myopathy, and cardiomyopathy in male patients. The phenotype is variable and mitigated in females. The timely identification of de-novo LAMP2 mutated family members, many of whom are heterozygous females, remains critical for their treatment and family counseling. DD laboratory testing builds on minimally invasive quantification of the LAMP2 protein in white blood cells and characterization of the specific mutation. This integrative approach is particularly helpful when assessing suspect female heterozygotes. LAMP2 exon-copy number variations (eCNVs) were so far reported only in X-hemizygous male DD probands. In heterozygous female DD probands, the wild-type allele may hamper the identification of an eCNV even if it results in the complete abolition of LAMP2 transcription and/or translation. To document the likely underappreciated rate of occurrence and point out numerous potential pitfalls of detection of the LAMP2 eCNVs, we present the first two DD heterozygote female probands who harbor novel multi-exon LAMP2 deletions. Critical for counseling and recurrence prediction, we also highlight the need to search for somatic-germinal mosaicism in DD families.

Review: Danon disease: Review of natural history and recent advances

“…The majority were null (nonsense, frame‐shifting deletions/insertions) or splicing mutations. Missense mutations (only nine reported) and large rearrangements involving one or more exons were rare. A synonymous substitution (c.864G> A) caused exon 6 skipping, indicating that apparently silent variations may be damaging when localized close to the splice sites .…”

Danon disease is an underdiagnosed cause of advanced heart failure in young female patients: a LAMP2 flow cytometric study

“…Importantly, characterization of the LAMP2 mutations in DD patients #3 and #4 mandated an individualized methodological approach that was far beyond the standard WES analytics in both patients. 13,14 WES testing was negative or inconclusive in 21 patients (47%). Table 2 summarizes the molecular genetic analyses, WBC XCI, and myocardial LAMP2 IHC findings in the female DD patients.…”

“…10 Patients #2 and #3 carried heterozygous deletion exon copy number variants encompassing LAMP2 exons 4-9C and 4-8, respectively. 13 Patient #4 had an Xq24 re-arrangement that caused a heterozygous deletion of several C-terminal exons of CUL4B and the complete deletion of LAMP2, ATP1B4, TMEM255A, and ZBTB33 genes. 14 Patient #5 was heterozygous for a novel frameshift c.445_449delGACCT mutation in the LAMP2 exon 4 (Supporting Information, Figure S1A).…”

“…XCI triggers mosaic expression of the wild-type and mutant LAMP2 alleles in tissues of female DD patients ( Figure 1B, C). 10,[12][13][14] Setting thresholds for skewing or extreme skewing of XCI is arbitrary. Importantly,~98% of females have WBC XCI ratios within the >5:95/<95:5 range.…”

“…copy number variants) can be easily missed. 13 Contrary to these high-throughput genomic analytical techniques, the outlined FC method is a selective protein-level expression test. Unlike to analyses of WBCs homogenates by western blotting, 8 the fraction of LAMP2def cells is directly quantified by the FC method.…”