Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

Abstract

Key Clinical MessageClinical diagnostic exome sequencing (DES) is currently infrequently used for detecting uniparental disomy (UPD). We present a patient with a dual diagnosis of GLI2 haploinsufficiency as well as UPD of chromosome 20, both identified through DES. We therefore recommend routine UPD analysis during DES to identify this genetic aberration.

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

“…Another observation that may be helpful in recognizing UPD(20)mat patients is the advanced maternal age. Consistent with previous reports [ 10 , 13 , 14 , 15 , 16 ], our study confirms the association of maternal UPD with advanced maternal age, which is recorded > 40 years (mean maternal age = 42 years) for all three patients. The phenomenon may be explained considering that trisomy 20 mosaicism is one of the most frequent cytogenetic abnormalities observed in amniocentesis or chorionic villus sampling [ 25 ].…”

“…Interestingly, two of them displayed growth hormone deficiency. These data confirm the pre- and postnatal growth failure and feeding difficulties previously described as main shared features by all UPD(20)mat cases [ 10 , 13 , 14 , 15 , 16 , 17 ]. Interestingly, only patient 1 displayed body asymmetry and only patient 2 had relative macrocephaly at birth: this latter parameter was achieved only in 10 cases among the reported ones and was present in 4 of them.…”

“…Even if the number is still limited, this trait, so distinctive of SRS, is found in less than 50% of UPD(20)mat, with NH-CSS ≥ 3 SRS patients (as calculated in at least 15/21 reported patients). Furthermore, all of our patients showed small and triangular facies, 2/3 showed micrognathia, and 2/3 showed muscular hypotonia, and minor characteristics were also present with sporadic frequency in the cases described so far [ 10 , 13 , 14 , 15 , 16 , 17 ].…”

“…UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome (MBCS), OMIM #617352) is a poorly characterized condition: only 18 non-mosaic and 3 mosaic cases, including a description of their clinical phenotypes [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] have been reported. The patients shared severe feeding difficulties associated with failure to thrive and intrauterine/postnatal growth retardation.…”

Homozygosity for a Novel DOCK7 Variant Due to Segmental Uniparental Isodisomy of Chromosome 1 Associated with Early Infantile Epileptic Encephalopathy (EIEE) and Cortical Visual Impairment

“…While both UPhD and UPiD can result in imprinting disorders, only UPiD may lead to homozygosity of pathogenic sequence variants [11,12]. Since the first demonstration of UPiD in a patient with cystic fibrosis [11,[13][14][15][16][17][18][19][20][21], an increasing number of incidental findings of autosomal recessive diseases caused by UPiD have been documented.…”