Fig 1.
Pedigree and mutation segregation.
All patients exhibiting symptoms of HHR are homozygous for the mutation SLC34A3 p.G196R (c.586G>A NM_080877.2), whereas all patients expressing symptoms of CM are homozygous for the mutation SEPN1 p.G239R (c.715G>A NM_206926.1). Therefore, patients II-2 and II-7 present features of both diseases. Arrows indicate index patients. Abbreviations: HHR = Hereditary hypophosphatemic rickets; CM = congenital myopathy.
Fig 2.
Histochemical and immunohistochemial biopsy analyses from affected family members and a normal control.
H&E staining of transverse cryostat sections displays findings well compatible with a slowly progressive myopathy with some replacement of muscle by fat in patients III-1 (A), II-2 (D), and II-7 (G); and is also abnormal in patient II-6 due to increased fiber variability (J) compared to a control (M). There is increased variability in fiber size in all family members (B,E,H,K) Notice also additional small atrophic fibers in patient II-2 (E), and some subsarcolemnal muscle fiber disorganization in patient II-7 (H arrow). NADH enzymehistochemistry depicts core like lesions in patients II-2 (F) and II-6 (I), and minor myofibrillar disorganization in patients III-1 (C) and II-6 (L).
Table 1.
Synopsis of clinical and paraclinical findings in patients II-2, II-6, II-7 and III-1.
Table 2.
Muscle morphology in patients II-2, II-6, II-7 and III-1.
Fig 3.
(A) Top: The SEPN1 p.G239R (c.715G>A NM_206926.1) mutation is located in a large, continuous segment of homozygosity identified in patients II-2 and II-7 of 33Mb (chr1:22Mb-55Mb). Bottom: Schematic representation of the mapped sequencing reads of the p.G239R mutation. (B) Top: Linkage analysis of all patients with symptoms of HHR (II-2, II-6 and II-7) yielded maximum genome-wide two-point and multi-point LOD score of 1.62 on 9q34, indicated by green line, harboring the SLC34A3 p.G196R (c.586G>A NM_080877.2) mutation identified in II-2 and II-7. Bottom: Schematic representation of the mapped sequencing reads of the SLC34A3 c.586G>A (NM_080877.2) variant.
Fig 4.
Co-occurrence of two recessive diseases under consanguinity.
Probabilities are calculated for a model of two recessive diseases, each being caused by a single fully penetrant locus with identical susceptibility allele frequency, q, and both loci being unlinked. (A) Log10 value of the probability to observe two recessive diseases in a single family by chance as a function of consanguinity level FI in the general population and the same risk allele frequency, q, at both unlinked loci. (B) Log10 value of the increase in the co-occurrence probability due to consanguinity compared to the non-consanguineous case (FI = 0). Probabilities and allele frequencies are depicted using their decadic logarithm (log10). For example, when assuming values of FI = 0.01 and q = 0.001 = 10−3, the two diseases will jointly occur in a single family with a probability of roughly 10−10, which equals approximately an 102 = 100-fold increase in probability in comparison to a non-consanguineous population.