A distinctive phenotype associated with an interstitial deletion 6q14 contained within a de novo pericentric inversion 6 (p11.2q15)

Abstract

This report describes a nearly 25-year-old female with an interstitial deletion of band 14 in the long arm of one chromosome 6 (6q14). The deletion is contained within a de novo pericentric inversion with breakpoints in 6p11.2 and 6q15 (Karyotype 46,XX, del(6)(q13q15),inv(6)(p11.2q15). The distal breakpoint of the deletion and the pericentric inversion at 6q15 are the same, but the proximal breakpoints differ. Since cells with other chromosomal findings were not detected in cultured lymphocytes and fibroblasts, chromosome mosaicism seems unlikely. Thus, it is assumed that the inversion and the deletion originated from the same event. The development of a distinctive phenotype in the patient was observed over a period of 22 years. It includes characteristic dysmorphic facial features such as ocular hypertelorism, flat nasal bridge, prominent zygomatic bones, and a depressed glabella. A striking, non-progressive deficit of motor control is manifest in an inability to use her hands properly and a broad-based slow-motion-like gait. Although severely deficient in abstract mental abilities and speech development, she is well adapted to family life and to a school for retarded individuals. Normal height and head circumference, and reduced sensitivity to pain are noteworthy. Presumably the deletion caused the phenotype and the distinct behavioral pattern. This patient probably represents a novel chromosomal phenotype that results from aggregate haploinsufficiency of gene loci in the deleted region.

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…The first case was a de novo CCR involving multiple deletions in association with a pericentric inversion of chromosome 6 [Passarge, 2000;Poot et al, 2009;Kloosterman et al, 2012]. Initially, this patient was described as a case with a pericentric inversion of 6p11.2;q15 with an additional deletion within 6q14, which upon SNP-array analysis was found to harbor 3, instead of 1, deletions within the de novo pericentric inversion ( fig.…”

“…Initially, this patient was described as a case with a pericentric inversion of 6p11.2;q15 with an additional deletion within 6q14, which upon SNP-array analysis was found to harbor 3, instead of 1, deletions within the de novo pericentric inversion ( fig. 2 ) [Passarge, 2000;Poot et al, 2009]. The patient's phenotype consists of a dysmorphic face, nonprogressive deficit of motor control, lack of speech development, and a strongly reduced sensitivity to pain [Passarge, 2000;Poot et al, 2009].…”

“…2 ) [Passarge, 2000;Poot et al, 2009]. The patient's phenotype consists of a dysmorphic face, nonprogressive deficit of motor control, lack of speech development, and a strongly reduced sensitivity to pain [Passarge, 2000;Poot et al, 2009]. Following a gene-centric approach, only haploinsufficiency of deleted genes or the disruption of the MUT gene by the leftmost breakpoint of deletion 1 ( table 4 ) would be considered [Poot and Hochstenbach, 2010;Poot et al, 2011a].…”

“…Not only the detection rate of CCRs increased, they were also more often associated with CNVs than reciprocal translocations were [Feenstra et al, 2011]. An example of advancing insights into a CCR by progressively improving resolution is a case, which initially was reported as an 'interstitial loss 6q14 contained within a de novo pericentric inversion 6(p11.2q15)', but eventually became a 10-breakpoint CCR [Passarge, 2000;Poot et al, 2009;Kloosterman et al, 2012]. On the other hand, if genome aneuploidy screening is limited to arrays only, we may miss some of the CCRs or may misinterpret their nature and complexity [Hochstenbach et al, 2009;Brand et al, 2014].…”

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

“…4,9 Only one case of an individual with a neurodevelopmental disorder involving the GABA A cluster on 6q15 (GABRR1 and GABRR) has been reported. 10 This 22-year-old female had intellectual disability, ataxia and severe speech deficiency, with an inversion and a deletion described as 46,XX, del(6)(q13q15),inv(6)(p11.2q15 46,XX, del(6)(q13q15),inv(6)(p11.2q15). We are not aware of any previous reports of CNVs among individuals with a neurodevelopmental disorder in the GABA A cluster at 5q34-35.1 (GABRB2, GABRA6, GABRA1, GABRG2 and GABRP).…”