Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies

Abstract

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.

Keywords: chromatin remodeling; epilepsy; microcephaly.

FIGURE 1

Schematic of variants in the (a) BPTF gene and (b) BPTF protein. Variants in black represent variants reported previously. Variants in red represent variants described in the present study [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

(a) Patient 1, (b) Patient 2, (c) Patient 5, (d) Patient 12, (e) Patient 17, (f) Patient 18, (g) Patient 19, (h) Patient 20, (i) Patient 21 at age 9 years 10 months, (j) Patient 21 at age 10 years 3 months, (k) Patient 22 at age 8 years(Midro et al., 1993), (l) Patient 22 at age 35 years (Midro et al., 2019), (m) Patient 23, (n) Subject 5 from Stankiewicz et al., 2017 (Stankiewicz et al., 2017). Note the presence of prominent nasal ridge (a, b, c, e, g, h, i, k, l, n), bulbous nasal tip (a, d, h, k, m, n), and pointed chin (a, c, d, e, f, i, k, m, n) [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

(a) Patient 12, (b) Patient 17, (c) Patient 18, (d) Patient 19, (e) Patient 20, (f) Patient 22, (g) Patient 1, (h) Patient 12, (i) Patient 17, (j) Patient 18, (k) Patient 20, (l) Patient 22. Note the presence of fifth finger clinodactyly (d), sandal gap deformity (i, k) and cutaneous syndactyly (j, k) [Color figure can be viewed at wileyonlinelibrary.com]