Schematic representation of the CHD7 mutations identified so far. The mutations found by Vissers et al8 are shown in orange; the ten nonsense mutations found in our cohort are shown in blue. Circles indicate the nonsense mutations, squares the missense mutations, and triangles the intron‐exon boundary mutations. On the bottom, functional CHD7 domains are indicated: chromodomains in red, SNF2 domain in green, and helicase domain in yellow.

 (A) External ear dysmorphism in the 10 fetuses. Note the characteristic triangular or square shaped and wrinkled morphology in all cases. (B) Normal (on the left) and pathological (on the right) view of three of the major clinical findings, namely severe semicircular canal hypoplasia (b: fetus 10) on profile babygram at 19 weeks (control at 19 weeks), arhinencephaly (d: fetus 10) at 34 weeks (control at 34 weeks), and retinal coloboma (f: fetus 1) at 19 weeks (control at 19 weeks). (C) Hands of fetus 9 showing the ectrodactyly. (These images are published with consent.)

 Expression of the CHD7 gene during human embryonic development. Adjacent sections are coloured with haematoxylin/eosin (X), treated with antisense or sense control riboprobes (X′ and X′′, respectively). Ventral to right, rostral to top where applicable. (A) At Carnegie stage (C)10, after 22 days (d) of development, CHD7 is expressed ubiquitously within embryonic but not extraembryonic tissues (cv) seen in transverse section. (B) By C11, expression is slightly more intense within the rhombencephalon, as observed in parasagittal section, but is not markedly present within the heart (h), liver (lv), or pharyngeal endoderm (pe). (C) A stronger signal is observed in the entire central nervous system (prosencephalon (pros) and rhombencephalon (rh)) by C14, including the diencephalic optic stalk (os), and is also seen in the cephalic mesenchyme (ms) of the frontonasal bud and pharyngeal arches (pa1, pa2). Heart expression is non‐existent/not found (h). The otic vesicle, negative at C12 (not shown), expresses CHD7 in its epithelium (ot) and associated acoustic ganglion (*) at this stage. Parasagittal section. (D) Enlargement of the body of the same C14 embryo shows a strong CHD7 signal in the spinal cord (sc) and dorsal root ganglia (drg), and a weak signal in limb bud mesenchyme (lb). (E) At C15, CHD7 expression is restricted to the dorsal epithelium of the otic vesicle (ot), presumptive inner ear, and the rhombencephalon (rh), spinal cord, and dorsal root ganglia (not shown); however, expression is barely above background in pharyngeal arch mesenchyme (pa1–3) and absent from the neural retina (nr), pharyngeal endoderm (pe), and nasal placode (np). (F, G) By C19, the CHD7 signal becomes intense in the entire neural retina (nr), rhombencephalon (rh), anterior pituitary gland (pit), diencephalon (di; in particular the hypothalamus (hyp)), and olfactory nerve (on, arrowhead) and bulb and is more discrete but distinct within the semicircular canals (scc). Expression continues to be absent from any portion of the heart (h). md, mandible; tg, tongue. (H) At 9 weeks of development (wd), CHD7 transcripts are detectable in the nasal epithelium (ne) but not within the nasal septum (ns) in coronal section. (I) Also at 9 wd, CHD7 expression is observed in neuronal soma of the neural retina in contrast to the absence of signal in the axon fascicles at the optic papilla (pp) and nerve (on), although the outer sheath of the nerve continues to express CHD7 (compare frame C′). (J) An enlargement of the pituitary gland in the same coronal section as (I) demonstrates continued CHD7 expression within anterior and median lobes at 9 wd.