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A de novo ATXN2L variant in a child with developmental delay and macrocephaly

To the Editor, Macrocephaly is an important clinical sign in patients with developmental delay as it helps with the differential diagnosis. Overgrowth syndromes, where developmental delay is common, are characterized by macrocephaly and long stature. However, there are many developmental delay conditions in which macrocephaly is not accompanied by other overt signs of overgrowth, and these tend to be linked to the mTOR pathway, which serves as a master regulator of cellular metabolism and proliferation (Liu & Sabatini, 2020). Examples include PTENrelated autism/macrocephaly syndrome, AKT3and PIK3R2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, PIK3CA-related megalencephaly-capillary malformation-polymicrogyria syndrome, MTOR-related Smith-Kingsmore syndrome, TBC1D7-related macrocephaly/megalencephaly syndrome and STRADA-related polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (Dobyns & Mirzaa, 2019). Here, we propose a new macrocephalydevelopmental delay syndrome potentially caused by a de novo variant in ATXN2L, which has been shown to modulate the mTOR pathway. The index patient was first referred to clinical genetics at age 17 months due to macrocephaly and developmental delay. His pregnancy was complicated by gestational diabetes managed with diet only and the prenatal finding of macrocephaly with no evidence of hydrocephalus. Delivery was via cesarean section at 36 weeks and 6 days due to macrocephaly and breech presentation. Parents were reassured that the macrocephaly was “benign” due to lack of hydrocephalus on brain imaging. Unfortunately, birth OFC and early imaging studies were not available. Macrocephaly progressed and there were signs of global developmental delay that prompted his referral to us when he was unable to make single words and did not make his first steps, although he did show signs of engagement. Physical examination revealed severe macrocephaly (OFC 53.7 cm, +4.6 SD), short stature (71.8 cm, −2.9 SD), normal weight (10.1 kg, 11th centile), high forehead, scant eyebrows, depressed nasal bridge, right hemihypertrophy, and central hypotonia (Figure 1). A follow up developmental assessment revealed moderate intellectual disability and no signs of autism. CT brain at age 21 months revealed dilated lateral and third ventricles, normal fourth ventricle, cerebellar tonsils approaching the level of the foramen magnum and unfused sutures. A follow up MRI at age 23 months was consistent with the CT findings (Figure 1). Chromosomal microarray was normal and exome sequencing did not reveal any pathogenic variants in relevant genes. However, trio exome sequencing revealed a de novo variant in ATXN2L [NM_148414.2: c.3017C>T;p.(Pro1006Leu)], which was confirmed by Sanger sequencing (Figure 1). This variant is highly conserved, predicted deleterious in silico (SIFT 0.002, PolyPhen 0.965, MutationTaster 1.00, and CADD 26.9), and absent in gnomAD and in our local exome database. At the gene level, ATXN2L appears to be intolerant to haploinsufficiency with pLI score of 1. ATXN2L is a homolog of ATXN2, and while the latter is linked to spinocerebellar ataxia and amyotrophic lateral sclerosis through polyglutamine expansions, the former is yet to be linked to a specific human phenotype. The two genes are phylogenetically conserved and have been shown to play a role in RNA surveillance enabled by their RNA-binding Lsm and LsmAD motifs and PABPC1-binding PAM2 motif (Satterfield & Pallanck, 2006; Yokoshi et al., 2014). Clues about the potential involvement of ATXN2L in macrocephaly come from nematodes in which atx-2, the single ortholog for both ATXN2 and ATXN2L, was found to repress mTOR signaling (Bar et al., 2016). Specifically, knockdown of atx-2 reverses the slow growth induced by dietary restriction and this is thought to be mediated by loss of mTOR inhibition normally achieved by its interaction with GDI-1 (GDI2 in humans) (Bar et al., 2016). It is surprising, therefore, that homozygosity for a presumably loss of function Atxn2l allele is embryonic lethal in mouse with significant growth deficiency (Key et al., 2020). The authors could not fully explain the paradoxical effect of ATXN2L deficiency in mouse embryos as compared with the published nematode Received: 11 November 2020 Accepted: 14 November 2020