Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples

Abstract

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.

Keywords: FAT1; KATNB1; consanguinity; lissencephaly 6; microcephaly; microphthalmia; next generation sequencing; preaxial polydactyly; split foot.

Figure 1

(A,B) Microcephaly, slight posterior plagiocephaly, bilateral ptosis, nystagmus, anteverted nostrils and down-turned corners of the mouth. (C–F) Hands: single palmar crease on the left hand, slight bilateral clinodactyly of the 5th finger. Feet: slight cutaneous syndactyly of second–third toes on the right foot. (G–L) Brain MRI (age 3 months): subarachnoid dilatation and abnormal gyration in the fronto-temporal regions, slight hippocampal malrotation, subcortical heterotopia, slightly thickened cerebral cortex. (M) Somatometric data at birth, 11 months, 2 years and 3 months, 3 years and 10 months of age.

Figure 2

(A–E) Clinical examination at birth: normal head, severe bilateral microphthalmia. (F–H) Preaxial polydactyly on the right hand. (I–K) Right split foot with four toes and third–fourth syndactyly and on the left foot: second toe polydactyly with nail. (L–N) Skeletal X-ray: no vertebral anomalies, no long bone anomalies. (O–R) Right hand X-ray: preaxial polydactyly with one metacarpal and two proximal and distal phalanges; right foot X-ray: split foot with four toes and five metatarsals: curved second metatarsal; left foot X-ray: second toe polydactyly. (S,T) Brain MRI: Bilateral enophthalmos with markedly dysmorphic appearance of the eyeballs with profile irregularities in particular on the posterior part in correspondence with the head region of the optic nerve and bilateral coloboma. On the left, dysmorphic appearance and posterior displacement of the lens, anchored to the ciliary body/suspensory ligaments that appear stretched with secondary enlargement of the anterior chamber; on the posterior side the lens appears deformed and attracted posteriorly in relation to the persistence of the hyaloid canal (persistent hyperplastic primary vitreous body, PHPV). More nuanced and slender PHPV finding is also evident in the right eyeball where the posterior surface of the lens appears slightly dysmorphic. The optic nerves (with a slightly tortuous course in the retrobulbar tract) are appreciable bilaterally, the chiasm and the optic tracts are also regularly displayed. (U) Somatometric data at birth and at 10 months of life.