Further delineation of genotype–phenotype correlation in homozygous 2p21 deletion syndromes: First description of patients without cystinuria

Abstract

Homozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia-cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions including the cystinuria gene SLC3A1 and the adjacent PREPL gene. Larger homozygous deletions in this region encompassing the PPM1B, SLC3A1, PREPL, and C2orf34 (CAMKMT) genes result in a more severe phenotype, the 2p21 deletion syndrome. A phenotype intermediate to HCS and the 2p21 deletion syndrome is termed atypical HCS and is caused by deletion of SLC3A1, PREPL, and C2orf34 (CAMKMT). Using high resolution SNP array molecular karyotyping we identified two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the SLC3A1 gene. The affected siblings display a recognizable phenotype which is similar to atypical HCS with regard to growth failure and neuro-muscular features, but is characterized by lack of cystinuria. The patients also exhibit features which have not been reported to date such as cleft palate and genital abnormalities. In conclusion, we report the first patients with a homozygous 2p21 deletion syndrome without cystinuria and further delineate the complex genotype-phenotype correlations of homozygous microdeletion syndromes of this region.

The clinical significance of small copy number variants in neurodevelopmental disorders

“…Pathogenic homozygous CNVs are more commonly described in consanguineous families, but limited data are available on the genome-wide estimate of these CNVs with a reported frequency of ∼0.009% in a cohort of diverse clinical phenotype52 and ∼0.5% in 194 patients with ASD 53. Here, both of our homozygous deletions were detected in patients of non-consanguineous parents of Swiss origin, the homozygous 2p21 deletion at the border of a 7.6 Mb loss of heterozygosity (LOH) region37 and the ACOT7 exonic homozygous deletion flanked by two heterozygous single-nucleotide polymorphism within a 1.7 Mb interval. CNVs or mutations affecting ACOT7 have not been reported before; however, given the familial segregation and the overlap with the reported KO mice phenotype, we suggest that ACOT7 indeed causes a novel autosomal-recessive disorder characterised by mild ID, epilepsy and episodes of ravenousness and fatigue.…”

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

“…41 Deletions that were limited to SLC3A1 and PREPL showed no reduction in OXPHOS activity, with the exception of a single patient out of a group of 22 who showed a reduction in complex V activity. [42][43][44][45][46] Patients with a deletion encompassing only PREPL and CAMKMT showed elevated lactate and hypotonia, suggesting mitochondrial involvement, but OXPHOS enzyme activity were not measured. 42 When assessing combinations of deletions and the corresponding OXPHOS enzyme characterization that has been published, our deduction indicates that of the 4 genes that are involved in the 2p21 deletion syndrome, a deletion of CAMKMT is present in most of the patients in which a mitochondrial phenotype has also been observed, suggesting that this gene is responsible for the mitochondrial connection with this syndrome.…”

PREPL Deficiency: A Homozygous Splice Site PREPL Mutation in a Patient With Congenital Myasthenic Syndrome and Absence of Ovaries and Hypoplasia of Uterus

“…Hypotonia-cystinuria syndrome has been described as a disorder with cystinuria and congenital myasthenic result from the recessive deletions in SLC3A1 and PREPL (Jaeken et al, 2006;Régal et al, 2014;Legati et al, 2016;Tucker et al, 2019). To date, only 10 patients with isolated PREPL deficiency (Jaeken et al, 2006;Régal et al, 2014Régal et al, , 2018Laugwitz et al, 2018;Silva et al, 2018 6 ) and 21 HCS families (contiguous deletion, including the SLC3A1 and PREPL genes) have been reported (Clara and Lowenthal, 1966;Polgár, 2002;Font-Llitjós et al, 2005;Szeltner et al, 2005;García-Horsman et al, 2007;Martens et al, 2007;Boonen et al, 2011;Eggermann et al, 2012;Régal et al, 2012Régal et al, , 2014Bartholdi et al, 2014;Wortmann et al, 2015). The most frequent characteristic features of subjects with PREPL deficiency are severe neonatal hypotonia, growth impairment and cognitive problems.…”

“…Hypotonia-cystinuria syndrome (HCS) is a very rare autosomal recessive disorder characterized by cystinuria, severe neonatal hypotonia, growth impairment, and cognitive problems (Jaeken et al, 2006;Martens et al, 2007;Bartholdi et al, 2014). This syndrome is caused by recessive deletions of SLC3A1 and PREPL genes on chromosome 2p21 (Régal et al, 2012).…”