Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility

Abstract

We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and to asses diagnostic yield and clinical impact in patients with suspected genetic diseases. Local physicians ascertained pediatric patients who had no previous access to genetic testing. More than 1586 genetic tests were performed in 1019 individuals (349 index cases, 670 relatives). Most frequently performed tests were exome/genome sequencing (ES/GS, 284/78 index cases) and specific gene panels (55 index cases). In 61.3% of the patients (n = 214) a genetic diagnosis was established based on pathogenic and likely pathogenic variants. Diagnostic yield was higher in consanguineous families (60.1 vs. 39.5%). In 27 patients, genetic diagnosis relied on additional biochemical testing, allowing rapid assessment of the functional effect of the variants. Remarkably, the genetic diagnosis had a direct impact on clinical management. Most relevant consequences were therapy related such as initiation of the appropriated treatment in a timely manner in 51.9% of the patients (n = 111). Finally, we report 12 candidate genes among 66 cases with no genetic diagnosis. Importantly, three of these genes were validated as ‘diagnostic’ genes given the strong evidence supporting causality derived from our data repository (CAP2-dilated cardiomyopathy, ITFG2-intellectual disability and USP53-liver cholestasis). The high diagnostic yield, clinical impact, and research findings demonstrate the utility of genomic testing, especially when used as first-line genetic test. For patients with suspected genetic diseases from resource-limited regions, ES can be considered as the test of choice to achieve genetic diagnosis.

Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary

“…By adding the phenotypic and molecular data of a further four patients to the 19 described to date [ 7 , 8 , 9 , 10 ], we aimed to expand the clinical and molecular knowledge on this rare entity. We did not see a geographical accumulation of the patients within Hungary; they originated from different parts of the country.…”

“…This homozygous 3-bp deletion in the promoter of the UFM1 gene has further been described in other patients with AR Hypomyelinating leukodystrophy type 14, presenting with microcephaly, hearing impairment, seizures, and global developmental delay, co-segregating in affected sibling and detected by genome sequencing (reported as NM_001286704.1( UFM1 ):c.-273_-271del) [ 8 ] in Pakistani (reported as NC_000013.10 (NM_016617.2):c.-155_-153del) [ 9 ] and Slovenian patient(s) with progressive neurodegenerative disease (reported as NM_016617.2( UFM1 ):c.-155delTCA) [ 10 ]. The Slovenian patient had profound intellectual disability and epilepsy with a history of apnoeic episodes and feeding difficulties in infancy.…”

A Novel Homozygous USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature

“…Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Up to now, a total of 29 cases from 22 families have been reported in 6 articles in the literature showing that the USP53 gene is associated with cholestasis and/or some additional phenotypes [5,7,[18][19][20][21]. Detailed clinical, laboratory, and genetic ndings of all cases reported in the literature and our own case (totally 30 cases) are summarized in Table-2.…”

Two Novel Mutations in the SI Gene Associated With Congenital Sucrase-Isomaltase Deficiency: A Case Report in China

“…Patients with an onset of CSID in childhood or adulthood present milder symptoms with only chronic diarrhea and have normal growth rates (11). According to a summary of previously reported cases (2,(6)(7)(8)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), the incidence of CSID differs between females and males (19/60) (Table 1). However, in some of these cases, sex was not reported.…”