Homozygous loss‐of‐function variants of TASP1 , a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies

Abstract

We report four unrelated children with homozygous loss‐of‐function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure‐to‐thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5–11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann–Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease‐related gene.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

“…Due to syndromic short stature, hypertrichosis with long eyelashes and prominent eyebrows, WSS has phenotypic overlap with CdLS, Kabuki syndrome, Rubinstein‐Taybi syndrome, and Coffin‐Siris syndrome (Aoi et al, 2019; Bramswig et al, 2015; Homma et al, 2019; Negri et al, 2019). Homozygous LoF variants in TASP1 , which cleaves and activates KMT2A, should be considered in the differential diagnosis of WSS due to the overlapping phenotype of DD, hypotonia, microcephaly, feeding difficulties with failure‐to‐thrive, recurrent respiratory infections, cardiovascular malformations, happy demeanor, and distinctive facial features (Suleiman et al, 2019). Two patients in this cohort had previously been provisionally diagnosed with Dubowitz syndrome, a well‐established recognizable malformation syndrome, that has increasingly been recognized to be clinically diverse and etiologically heterogeneous (Innes et al, 2018).…”

A decade of next‐generation sequencing in genodermatoses: the impact on gene discovery and clinical diagnostics*

“…WES may also miss critical exons in disease‐associated genes as it is estimated to cover only around 80–85% of the exome sufficiently 58 . Indeed, several studies have failed to identify mutations via WES due to this incomplete coverage 68–74 . For genetically heterogeneous conditions with well‐defined disease‐associated genes, NGS‐based targeted gene panels have been used as a more reliable alternative to the relatively shotgun‐based approach of WES.…”

“…58 Indeed, several studies have failed to identify mutations via WES due to this incomplete coverage. [68][69][70][71][72][73][74] For genetically heterogeneous conditions with well-defined disease-associated genes, NGS-based targeted gene panels have been used as a more reliable alternative to the relatively shotgun-based approach of WES. Although it cannot be used as broadly, this targeted approach demonstrates better coverage of candidate genes, has faster turnaround times, and generates fewer incidental findings than WES.…”

Taspase1 orchestrates fetal liver hematopoietic stem cell and vertebrae fates through cleaving TFIIA

“…Recently, a novel human hereditary anomaly syndrome was recognized in association with loss-of-function mutations in the TASP1 gene ( 1 – 3 ). Those patients were characterized with microcephaly, developmental delay, distinctive facial features, and other anomalies, including anemia, thrombocytopenia, and lymphocytopenia ( 2 , 3 ). TASP1 codes for Taspase1, which is an evolutionarily conserved threonine protease that cleaves and regulates nuclear proteins, most notably, MLL (KMT2A, also known as MLL1) and TFIIAα-β ( 4 – 6 ).…”