Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar‐vermis hypoplasia

Abstract

We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense (c.770T>C, p.[Leu257Pro]) variant in the hedgehog acyl‐transferase gene (HHAT), encoding an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long and short range hedgehog signaling. There is a report of one family with Nivelon–Nivelon–Mabille syndrome in which HHAT was proposed as the likely candidate gene. The phenotypic overlap with the family we report herein provides further evidence implicating HHAT in cerebellar development and the pathogenesis of this rare spectrum.

Hedgehog acyl‐transferase‐related multiple congenital anomalies: Report of an additional family and delineation of the syndrome

“…The overlapping phenotypes in the previous two families and the present family include microcephaly, short stature, elevated creatinine phosphokinase levels, and skeletal dysplasia. Small cerebellar vermis was reported in the previous two families ( Abdel-Salam et al, 2019;Callier et al, 2014). Alobar holoprosencephaly and a single median central incisor are reported only in the present family, and no other signs of holoprosencephaly were noted previously in individuals with variants in HHAT.…”

“…Subsequently, Abdel-Salam et al described a second family with two affected female siblings with microcephaly, small cerebellar vermis, seizures, and skeletal dysplasia. In this family, they identified a biallelic missense variant, c.770C>T, p.(Leu257Pro), in exon 7 of HHAT (NM_001122834.3) as the likely cause of the multiple malformation syndrome (Abdel-Salam et al, 2019). The Leu257 residue also lies in the MBOAT domain.…”

Identification of novel candidate pathogenic genes in pituitary stalk interruption syndrome by whole‐exome sequencing

“…HHAT is a hedgehog acyltransferase, required for the post‐translational palmitoylation of Hedgehog proteins. Abdel‐Salam et al 21 reported a biallelic novel missense HHAT variant that might cause syndromic microcephaly and cerebellar‐vermis hypoplasia. HHAT mutations can also be indicative of severe acrania‐holoprosencephaly‐agnathia craniofacial defects.…”

FBW7 couples structural integrity with functional output of primary cilia

“…Interestingly, bi-allelic loss-of-function variations in SMO or Hedgehog acyl-transferase (HHAT) genes in humans led to many developmental anomalies including microcephaly 56,57 . While it is unknown whether microcephaly in humans caused by inactivating mutations in NDE1 is due to abnormally long cilia and/or reduced Hedgehog activity (GLI2), our data lend support to this idea.…”