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. 2020 Jul;98(1):91-98.
doi: 10.1111/cge.13765. Epub 2020 May 15.

HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome

Sara C Reichert  1 , Rachel Li  1 , Scott A Turner  2 , Richard H van Jaarsveld  3 , Maarten P G Massink  3 , Marie-José H van den Boogaard  3 , Mireia Del Toro  4 , Agustí Rodríguez-Palmero  5 , Stéphane Fourcade  5   6 , Agatha Schlüter  5   6 , Laura Planas-Serra  5   6 , Aurora Pujol  5   6   7 , Maria Iascone  8 , Silvia Maitz  9 , Lucy Loong  10 , Helen Stewart  10 , Elisa De Franco  11 , Sian Ellard  12 , Julie Frank  13 , Raymond Lewandowski  1
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HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome

Sara C Reichert et al. Clin Genet. 2020 Jul.

Abstract

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.

Keywords: HNRNPH1 gene; congenital abnormalities; intellectual disability; microcephaly; whole exome sequencing.

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