Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP.

Katherine C Mackenzie,Frances Flinter,George A Tanteles,Martina Wilke,Zornitza Stark,Rachel Schot,Arve Vøllo,Andreas Syrimis,Alice S Brooks,Nayia Nicolaou,Erwin Brosens,Jacek Pilch,Yuying Zhao,Jan D H Jongbloed,Sahar Mansour,Robert M.w Hofstra ,Grazia M.s Mancini ,Eleni Zamba‐Papanicolaou,Andrew J Green ,Bianca M De Graaf ,Violetta Christophidou‐Anastasiadou,Dicky Halley,Maria M Alves

doi:10.1002/humu.24097

Abstract

Goldberg–Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype–phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)‐associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR‐associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease.

Highlights

Goldberg–Shprintzen syndrome (GOSHS; MIM# 609460) is a rare and severe autosomal recessive disorder, characterized by moderate intellectual disability, dysmorphic facial features, microcephaly, and axonal neuropathy
According to the guidelines established by the American College of Medical Genetics (ACMG), all truncating variants identified in our GOSHS patients are classified as pathogenic (Table S2)
Modifier variants in Rearranged during transfection gene (RET) (Chatterjee et al, 2016), Neuregulin 1 gene (NRG1), and Semaphorin 3A gene (SEMA3A) (Kapoor et al, 2015) may work as these modifying factors, as it has been shown for other syndromes (Chatterjee et al, 2016; De Pontual et al, 2007; Tang et al, 2016)

Summary

| INTRODUCTION

Goldberg–Shprintzen syndrome (GOSHS; MIM# 609460) is a rare and severe autosomal recessive disorder, characterized by moderate intellectual disability, dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose), microcephaly (head circumference < ‐2.5 SD), and axonal neuropathy. KIFBP is 621 amino acids long and contains two tetratricopeptide repeats It is involved in the axonal structure and outgrowth, microtubule dynamics, and cargo trafficking, functioning by binding with various microtubule‐associated proteins, such as kinesins and the superior cervical ganglia 10 (SCG10; Alves et al, 2010; Kevenaar et al, 2016; Lyons, Naylor, Mercurio, Dominguez, & Talbot, 2008; Wozniak, Melzer, Dorner, Haring, & Lammers, 2005). Previous studies have already investigated the effect of common variants located in intron 1 of RET in a series of patients diagnosed with a Mendelian syndrome where HSCR is part of the phenotype (de Pontual et al, 2006, 2007). We determined if the occurrence of HSCR in GOSHS can be explained by the presence of common modifier alleles

| MATERIALS AND METHODS

| RESULTS

| DISCUSSION