Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease

Abstract

CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties.

Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

“…The average time to publication for novel genes was 2·5 years. Seven novel phenotypes in known neuromuscular disorder genes were reported from our cohort: CHD7 , 51 SQSTM1 , 46 HSPB8 , 48 STIM1 , 50 GMPPB , 47 TNNT3 , 52 and TOR1AIP1 49 . Families from our cohort with novel disease genes and phenotypes were reported either by our group, by other groups b (timeline not available), or in collaboration c .…”

“…Confirmation of biallelic PYROXD1 variants as novel basis for congenital myopathy in five unrelated affected families required three cell and animal models of disease and 52 months of multidisciplinary research 45 . Seven novel phenotypes (4·6%; 7 out of 152) for known human disease genes which expand the published clinical spectrum were also identified in the cohort and are outlined in Figure 2 46–52 …”

“… 45 Seven novel phenotypes (4·6%; 7 out of 152) for known human disease genes which expand the published clinical spectrum were also identified in the cohort and are outlined in Figure 2 . 46 , 47 , 48 , 49 , 50 , 51 , 52 …”

“…From ~2016, we sought formal classification of variants from accredited diagnostic scientists and genetic pathologists according to the American College of Medical Genetics and Genomics (ACMG) guidelines. 33 Identification of a novel disease‐gene association, 40 , 41 , 42 , 43 , 44 , 45 or a novel gene‐phenotype expansion 46 , 47 , 48 , 49 , 50 , 51 , 52 was defined by peer‐reviewed publication.…”

“…45 Seven novel phenotypes (4Á6%; 7 out of 152) for known human disease genes which expand the published clinical spectrum were also identified in the cohort and are outlined in Figure 2. [46][47][48][49][50][51][52] Diagnoses involving splice-altering variants (36% diagnoses) were nine times more common than novel disease genes (4% diagnoses)…”