20 years Age of onset 3 years 9 years

38/20 20 0.225 95 16 2 1 1 3 4 L541P G1961E

31/19 17 0.1 102 9 3 2 2 3 4 L541P F655C

Cases 4–7

STGD1 represents the most prevalent inherited macul-opathy, estimated to occur in 1 in 10,000 individuals.

Therefore,a lower homozygous frequency in the BAP dataset than expectedbased on the AF in the general population indicates that a variantis mild

Therefore,a lower homozygous frequency in the BAP dataset than expectedbased on the AF in the general population indicates that a variantis mild

(http://genetics.bwh.harvard.edu/pph2/). In addition, mutation taster predicted both L168F and L168S variant as disease-causing with PROVEAN predictions of L168F (-2.767) and L168S (-4.083) as deleterious (https://www.mutationtaster.org/). As such, it was not surprising that the L168S variant patient had much more severe disease onset and rapid progression compared to other SCA34-causing ELOVL4 variants. For example, a patient carrying the T233M ELOVL4 variant was reported to develop ataxia starting at 15 years of age [10]. However, at the time of examination of this patient at 60 years of age, an MRI of the brain showed only subtle flattening of the ventral pons and mild cerebellar atrophy [10]. Another patient carrying the Q180P ELOVL4 variant developed ataxia in his mid-20 s and showed cerebellar and pontine atrophy [11]. Japanese patients also carrying the W256G variant developed gait ataxia between 13–56 years of age [12]. However, disease progression was reported to be very slow, and patients did not require assistance with walking with a walker or cane until the age of 60 years or older [12]. Taken together, it looks like the nature of the mutation and its effect on normal ELOVL4 function most likely through defects in VLC-FA biosynthesis or conformational changes in protein structure are critical to disease onset and severity of the pathologies.

(http://genetics.bwh.harvard.edu/pph2/). In addition, mutation taster predicted both L168F and L168S variant as disease-causing with PROVEAN predictions of L168F (-2.767) and L168S (-4.083) as deleterious (https://www.mutationtaster.org/). As such, it was not surprising that the L168S variant patient had much more severe disease onset and rapid progression compared to other SCA34-causing ELOVL4 variants. For example, a patient carrying the T233M ELOVL4 variant was reported to develop ataxia starting at 15 years of age [10]. However, at the time of examination of this patient at 60 years of age, an MRI of the brain showed only subtle flattening of the ventral pons and mild cerebellar atrophy [10]. Another patient carrying the Q180P ELOVL4 variant developed ataxia in his mid-20 s and showed cerebellar and pontine atrophy [11]. Japanese patients also carrying the W256G variant developed gait ataxia between 13–56 years of age [12]. However, disease progression was reported to be very slow, and patients did not require assistance with walking with a walker or cane until the age of 60 years or older [12]. Taken together, it looks like the nature of the mutation and its effect on normal ELOVL4 function most likely through defects in VLC-FA biosynthesis or conformational changes in protein structure are critical to disease onset and severity of the pathologies.