American Journal of Medical Genetics Part A

doi: 10.1002/ajmg.a.62289pmid: N/A

doi: 10.1002/ajmg.a.62290pmid: N/A

doi: 10.1002/ajmg.a.62291pmid: 35396912

doi: 10.1002/ajmg.a.62292pmid: 35396913

doi: 10.1002/ajmg.a.62293pmid: 35396914

Wang, Chunyan; Seltzsam, Steve; Zheng, Bixia; Wu, Chen‐Han Wilfred; Nicolas‐Frank, Camille; Yousef, Kirollos; Au, Kit Sing; Mann, Nina; Pantel, Dalia; Schneider, Sophia; Schierbaum, Luca; Kitzler, Thomas M.; Connaughton, Dervla M.; Mao, Youying; Dai, Rufeng;

Marwaha, Ashish; Costain, Gregory; Cytrynbaum, Cheryl; Mendoza‐Londono, Roberto; Chad, Lauren; Awamleh, Zain; Chater‐Diehl, Eric; Choufani, Sanaa; Weksberg, Rosanna

doi: 10.1002/ajmg.a.62650pmid: 35043535

Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual disability, skeletal anomalies, and postnatal growth restriction. The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20‐30% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, KMT2D and KDM6A. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome‐wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for KMT2D led to the identification of a cryptic variant in KDM6A by genome sequencing; for the other case, a DNAm signature different from KS led to the detection of another diagnosis in the KS differential, CDK13‐related disorder. This approach illustrates the clinical utility of DNAm signatures in the diagnostic workflow for the genome analyst or clinical geneticist—especially for disorders with overlapping clinical phenotypes.

Damseh, Nadirah; Dupuis, Lucie; O'Connor, Constance; Oh, Rachel Youjin; Wang, Yi Wen; Stavropoulos, Dimitri James; Schwartz, Sarah B.; Mendoza‐Londono, Roberto

doi: 10.1002/ajmg.a.62672pmid: 35128800

Ehlers–Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensible skin, hypermobile joints, easy bruisability, and fragility of the connective tissues. The diagnosis is based on clinical assessment and phenotype‐guided genetic testing. Most EDS subtypes can be confirmed by genetic testing except for hypermobile EDS. This study explored the utility of applying the 2017 EDS classification criteria and molecular genetic testing in establishing an EDS diagnosis in children. In this retrospective study, we reviewed 72 patients referred to a tertiary care center for evaluation of EDS who underwent one or more forms of genetic testing. Eighteen patients (18/72, 25%) met the clinical criteria for one of the EDS subtypes and of these, 15 (15/18, 83%) were confirmed molecularly. Fifty‐four patients (54/72, 75%) had features that overlapped EDS and other syndromes associated with joint hypermobility but did not fully meet clinical criteria. Twelve of them (12/54, 22%) were later shown to have a positive molecular genetic diagnosis of EDS. Different molecular genetic tests were performed on the cohort of 72 patients (EDS panel, n = 44; microarray, n = 25; whole exome sequencing [WES], n = 9; single gene sequencing, n = 3; familial variant testing, n = 10; other genetic panels n = 3). EDS panel was completed in 44 patients (61%), and a molecular diagnosis was confirmed in nine of the patients who satisfied criteria for one of the EDS subtypes (9/12, 75%) and in nine of the patients who did not fully meet criteria (9/32, 28%). We observed a correlation between generalized joint hypermobility, poor healing, easy bruising, atrophic scars, skin hyperextensibility, and developmental dysplasia of the hip with a positive molecular result. This study provides guidance for the use of molecular genetic testing in combination with the 2017 clinical diagnostic criteria in children presenting with EDS characteristics.

Cappuccio, Gerarda; Brunetti‐Pierri, Nicola; Clift, Paul; Learn, Christopher; Dykes, John C.; Mercer, Catherine L.; Callewaert, Bert; Meerschaut, Ilse; Spinelli, Alessandro Mauro; Bruno, Irene; Gillespie, Matthew J.; Dorfman, Aaron T.; Grimberg, Adda; Lindsay, Mark E.;

Morales, Jose Andres; Valenzuela, Irene; Cuscó, Ivon; Cogné, Benjamin; Isidor, Bertrand; Matalon, Dena R.; Gomez‐Ospina, Natalia

doi: 10.1002/ajmg.a.62648pmid: 35018708

WAC‐related intellectual disability (ID) is a rare genetic condition characterized by a spectrum of neurodevelopmental disorders of varying severity, including global developmental delay (GDD), ID, and autism spectrum disorder. Here, we describe five affected individuals, age range 9–20 years, and provide proof of pathogenicity of a novel splicing variant. All individuals presented with GDD, some degree of ID, and variable dysmorphism. Except for feeding difficulties, all patients were healthy without major congenital malformations or medical comorbidities. All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC. Three unrelated patients from different ethnic backgrounds shared the intronic variant c.381+4_381+7delAGTA, which was predicted to alter splicing and was initially classified as a variant of uncertain significance. Reverse transcription‐polymerase chain reaction analysis from one patient's cells confirmed aberrant splicing of the WAC transcript resulting in premature termination and a truncated protein p.(Gly92Alafs*2). These functional studies and the identification of several nonrelated individuals provide sufficient evidence to classify this variant as pathogenic. The clinical description of these five individuals and the three novel variants expand the genotypic and phenotypic spectrum of this ultrarare disease.