Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: Composite or expanded phenotype?

Abstract

Background In the last few years trio‐whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases. Moreover WES allows the detection of variants in multiple genes causing different genetic conditions in a single patient, in about 5% of cases. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition. Methods Trio‐WES was performed on a 4‐month‐old baby with a complex clinical presentation characterized by skeletal anomalies, congenital heart malformation, congenital hypothyroidism, generalized venous and arterial hypoplasia, and recurrent infections. Results WES detected two different homozygous variants, one in CEP57, the gene responsible for mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short‐rib thoracic dysplasia. Conclusion The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants. The report then highlights the role of WES in providing complete and fast diagnosis in patients with complex presentations of rare genetic syndromes, with important implications in the assessment of recurrence risk.

Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients

“…The reported double-diagnosed cases are a good illustration, on top of previously described ones [5][6][7][8], of how different genetic conditions and molecular mechanisms could combine in a single patient, causing peculiar and complex clinical pictures. In Table 1, we summarised the combined diagnoses and their contribution to the patient's phenotype of our eight cases together with two other cases previously published by Cianci et al [5] and Pezzani et al [7] and diagnosed in our laboratory as well.…”

“…Beyond large cohorts, a few single clinical reports in the literature described patients affected by comorbid conditions [ 5 , 6 , 7 , 8 ].…”

Mosaic variegated aneuploidy syndrome 2 with biallelic novel CEP57 splice site variation in Indian siblings: Expanding the clinical and molecular spectrum

“…apnea, narrow thorax, preaxial polydactyly, syndactyly and mild intellectual disability. 1,3,[8][9][10][11] Facial dysmorphism, rhizomelic shortening of limbs and abnormal skull shape are the characteristic features observed in most of the affected individuals including our case. More than half of the patients (7/13) had congenital heart disease.…”

Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family

“…The majority of patients with MVA2 (8 out of 12) presented a homozygous 11-bp insertion in exon 9 (NM_014679.4: c.915_925dup11). Six of them were of Moroccan origin, 1 of them of Mexican, and 1 of Caucasian origin [Snape et al, 2011;Pinson et al, 2014;De la Torre-Carcia et al, 2019;Dery et al, 2020;Pezzani et al, 2020;Santos-Simarro et al, 2021]. A compound heterozygosity of the variant c.915_925dup11 in combination with a 2-bp deletion (c.520_521delGA) was reported as well [Snape et al, 2011].…”